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Hida T. Genomic profiling and personalized treatment strategies for skin malignancies: findings from the center for cancer genomics and advanced therapeutics database. Int J Clin Oncol 2025; 30:856-866. [PMID: 40156656 DOI: 10.1007/s10147-025-02755-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2025] [Accepted: 03/23/2025] [Indexed: 04/01/2025]
Abstract
Immune checkpoint inhibitors and molecular-targeted therapies have dominated recent cancer treatment. However, these treatments face challenges, such as primary and acquired resistance, indicating that not all patients benefit from them. Therefore, the search for new molecular targets is crucial. In addition, immune checkpoint inhibitors have exhibited racial differences in their effectiveness for certain neoplasms. Hence, understanding the genomic landscape of cancers in various racial groups is important. In Japan, health insurance has covered comprehensive genomic profiling since 2019, and the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) has accumulated genetic abnormalities along with clinical data of patients with various cancers. These data are crucial for advancing cancer research and drug development. This review discusses the genetic abnormalities of the major skin malignancies including melanoma, cutaneous squamous cell carcinoma (cSCC), and extramammary Paget's disease (EMPD), and proposes potential treatment strategies by comparing C-CAT data analysis with other genetic studies. The C-CAT data have emphasized unique genetic alterations in tumors of the Japanese population, particularly racial differences in tumor mutational burden in cutaneous melanoma and cSCC, indicating the importance of personalized treatment strategies that consider racial differences.
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Affiliation(s)
- Tokimasa Hida
- Department of Dermatology, Sapporo Medical University School of Medicine, South 1, West 16, Chuo-Ku, Sapporo, 060-8543, Japan.
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2
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Zhang Y, Zhang X, Shao W, Gao J, Xiang M, Wang Y, Liu M, Zhang W, Liang X. MEK inhibitors for the treatment of immunotherapy-resistant, AGK-BRAF fusion advanced acral melanoma: a case report and literature review. J Cancer Res Clin Oncol 2025; 151:133. [PMID: 40189647 PMCID: PMC11972992 DOI: 10.1007/s00432-025-06083-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2024] [Accepted: 01/05/2025] [Indexed: 04/09/2025]
Abstract
PURPOSE Acral melanoma (AM), a rare and aggressive melanoma subtype with poor prognosis, presents unique challenges in treatment due to its distinct molecular and immune characteristics. This case report describes a patient with AM harboring an AGK-BRAF fusion mutation, aiming to explore potential mechanisms of resistance to current treatment modalities. METHODS We analyzed tumor tissue samples from the primary and metastatic lesions of the patient using next-generation sequencing (NGS) for genomic profiling and multiplex immunohistochemistry (mIHC) to assess the immune microenvironment. The patient underwent multiple lines of treatment, including immunotherapy, chemotherapy, and targeted therapy, with their clinical outcomes documented and evaluated. RESULTS The AGK-BRAF fusion mutation and its reciprocal BRAF-AGK rearrangement were identified in both primary and metastatic tumors. Immune profiling revealed abundant CD8 + T cells, PD-L1 + cells, and CD68 + macrophages localized predominantly in the tumor interstitial region, potentially explaining the poor response to immunotherapy. Despite initial disease stabilization with trametinib and lenvatinib, rapid progression occurred, highlighting tumor heterogeneity and limited efficacy of combined therapies. CONCLUSION This case underscores the need for personalized approaches in treating AM, especially those with rare molecular alterations like AGK-BRAF fusion. Insights from genomic and immune profiling may inform future therapeutic strategies to overcome resistance and improve outcomes in this challenging melanoma subtype.
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Affiliation(s)
- Yanling Zhang
- Department of Medical Oncology, The Third People's Hospital of Zhengzhou, Zhengzhou, 450000, Henan, China
| | - Xifeng Zhang
- Department of Medical Oncology, The Third People's Hospital of Zhengzhou, Zhengzhou, 450000, Henan, China
| | - Weikang Shao
- Genecast Biotechnology Co., Ltd, Wuxi, 214000, China
| | - Ji Gao
- Department of Orthopaedics, The Third People's Hospital of Zhengzhou, Zhengzhou, 450000, Henan, China
| | - Mei Xiang
- Department of Medical Oncology, The Third People's Hospital of Zhengzhou, Zhengzhou, 450000, Henan, China
| | - Yan Wang
- Department of Medical Oncology, The Third People's Hospital of Zhengzhou, Zhengzhou, 450000, Henan, China
| | - Mengmeng Liu
- Department of Pathology, The Third People's Hospital of Zhengzhou, Zhengzhou, 450000, Henan, China.
| | - Weizhen Zhang
- Department of Medical Oncology, The Third People's Hospital of Zhengzhou, Zhengzhou, 450000, Henan, China.
| | - Xianbin Liang
- Department of Medical Oncology, The Third People's Hospital of Zhengzhou, Zhengzhou, 450000, Henan, China.
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Hiraki T, Hirakawa S, Otsuki Y, Kajimoto K, Goto K, Serizawa M. Fatal Spitz Melanoma With MAD1L1::BRAF Fusion: A Case Report and Literature Review. J Cutan Pathol 2025; 52:199-205. [PMID: 39723589 DOI: 10.1111/cup.14779] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Revised: 12/06/2024] [Accepted: 12/13/2024] [Indexed: 12/28/2024]
Abstract
Spitz melanoma is extremely rare, and only a few cases of distant metastases have been reported. Herein, we describe a case of Spitz melanoma with multiple distant metastases. A 37-year-old woman presented with a 5.5-mm-diameter nodule on the right lower leg. She experienced multiple distant metastases, involving the lungs, liver, thyroid, stomach, ovary, bones, and skin, along with multiple lymph node metastases within 1 year. The patient succumbed to the disease 1 year and 6 months following the first excision. Histopathological examination revealed a dense distribution of large solid nests comprising large, atypical epithelioid melanocytes with abundant eosinophilic cytoplasm in the upper dermis. Diffuse PRAME and loss of p16 immunoexpression profiles were observed. Targeted DNA and Sanger sequencing revealed an in-frame MAD1L1(e16)::BRAF(e9) fusion in both primary tumor and metastatic subcutaneous lesion. A review of previously reported cases confirmed as Spitz melanoma with distant metastases (n = 7) revealed a broad age range (11-71 years, median 46 years), high mortality (5/7), frequent BRAF fusions (6/7), and recurrent TERT promotor mutations and CDKN2A/B deletions. This report adds valuable insights into our understanding of the clinical and genetic characteristics of Spitz melanoma with distant metastases.
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Affiliation(s)
- Tsubasa Hiraki
- Department of Diagnostic Pathology, Shizuoka Cancer Center Hospital, Sunto, Japan
| | - Satoshi Hirakawa
- Department of Supportive Care in Cancer, Seirei Hamamatsu General Hospital, Hamamatsu, Japan
| | - Yoshiro Otsuki
- Department of Pathology, Seirei Hamamatsu General Hospital, Hamamatsu, Japan
| | | | - Keisuke Goto
- Department of Diagnostic Pathology, Shizuoka Cancer Center Hospital, Sunto, Japan
- Department of Diagnostic Pathology, Hyogo Cancer Center, Akashi, Japan
- Department of Pathology, Tokyo Metropolitan Cancer and Infectious Disease Center Komagome Hospital, Tokyo, Japan
- Department of Anatomic Pathology, Tokyo Medical University, Tokyo, Japan
- Department of Diagnostic Pathology, Chutoen General Medical Center, Kakegawa, Japan
- Department of Diagnostic Pathology and Cytology, Osaka International Cancer Institute, Osaka, Japan
- Department of Diagnostic Pathology, Osaka National Hospital, Osaka, Japan
- Department of Dermato-Oncology, National Hospital Organization Kagoshima Medical Center, Kagoshima, Japan
| | - Masakuni Serizawa
- Drug Discovery and Development Division, Shizuoka Cancer Center Research Institute, Sunto, Japan
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Javaid A, Peres T, Pozas J, Thomas J, Larkin J. Current and emerging treatment options for BRAFV600-mutant melanoma. Expert Rev Anticancer Ther 2025; 25:55-69. [PMID: 39784319 DOI: 10.1080/14737140.2025.2451722] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Revised: 01/06/2025] [Accepted: 01/07/2025] [Indexed: 01/12/2025]
Abstract
INTRODUCTION BRAF mutations are the most common driver mutation in cutaneous melanoma, present in 40% of cases. Rationally designed BRAF targeted therapy (TT) has been developed in response to this, and alongside immune checkpoint inhibitors (ICI), forms the backbone of systemic therapy options for BRAF-mutant melanoma. Various therapeutic approaches have been studied in the neoadjuvant, adjuvant and advanced settings, and there is a wealth of information to guide clinicians managing these patients. Despite this, certain challenges remain. AREAS COVERED We reviewed the available literature regarding BRAF mutation types and resistance mechanisms, neoadjuvant and adjuvant approaches for patients with early-stage disease, management of advanced disease, including patients with brain metastases, as well as identified areas of further research. EXPERT OPINION Although there is a significant amount of literature to guide the management of BRAF-mutant melanoma, several questions remain. Thus far, the management of stage III BRAF-mutant patients following neoadjuvant ICI, treatment de-escalation in long-term TT responders in the advanced setting and the management of symptomatic brain metastases remain areas of debate. Further work on predictive and prognostic biomarkers for patients with BRAF-mutant melanoma patients will assist in clinical decision-making.
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Affiliation(s)
- Anadil Javaid
- Skin and Renal Unit, Royal Marsden Hospital, London, United Kingdom
| | - Tobias Peres
- Skin and Renal Unit, Royal Marsden Hospital, London, United Kingdom
| | - Javier Pozas
- Skin and Renal Unit, Royal Marsden Hospital, London, United Kingdom
| | - Jennifer Thomas
- Skin and Renal Unit, Royal Marsden Hospital, London, United Kingdom
| | - James Larkin
- Skin and Renal Unit, Royal Marsden Hospital, London, United Kingdom
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5
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Hida T, Kato J, Idogawa M, Tokino T, Uhara H. Genomic landscape of cutaneous, acral, mucosal, and uveal melanoma in Japan: analysis of clinical comprehensive genomic profiling data. Int J Clin Oncol 2024; 29:1984-1998. [PMID: 39249554 DOI: 10.1007/s10147-024-02615-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Accepted: 08/22/2024] [Indexed: 09/10/2024]
Abstract
BACKGROUND Cutaneous melanoma (CM) is the most common type in Caucasians, while acral melanoma (AM) and mucosal melanoma (MM), which are resistant to immunotherapies and BRAF/MEK-targeted therapies, are more common in East Asians. Genomic profiling is essential for treating melanomas, but such data are lacking in Japan. METHODS Comprehensive genomic profiling data compiled in the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) were analyzed. RESULTS A total of 380 melanomas was analyzed, including 136 CM, 46 AM, 168 MM, and 30 uveal melanoma (UM). MM included conjunctival, sinonasal, oral, esophageal, anorectal, and vulvovaginal melanomas. No significant difference in the median tumor mutational burden (TMB) of CM (3.39 mutations/megabase), AM (2.76), and MM (3.78) was the key finding. Microsatellite instability-high status was found in one case. BRAF V600E/K was found in only 45 patients (12%). Key driver mutations in CM were BRAF (38%), NRAS (21%), NF1 (8%), and KIT (10%), with frequent copy number alterations (CNAs) of CDKN2A, CDKN2B, and MYC. AM was characterized by altered KIT (30%), NRAS (26%), and NF1 (11%) and CDKN2A, CDKN2B, CDK4, MDM2, and CCND1 CNAs. MM was characterized by altered NRAS (24%), KIT (21%), and NF1 (17%) and MYC, KIT, and CDKN2A CNAs, with differences based on anatomical locations. UM bore GNAQ or GNA11 driver mutations (87%) and frequent mutations in SF3B1 or BAP1. CONCLUSION The distinct genomic profiling in Japanese patients, including lower TMB, compared to Caucasians, is associated with poorer treatment outcomes. This result underscores the need for more effective therapeutic agents.
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Affiliation(s)
- Tokimasa Hida
- Department of Dermatology, Sapporo Medical University School of Medicine, South 1, West 16, Chuo-ku, Sapporo, 060-8543, Japan
| | - Junji Kato
- Department of Dermatology, Sapporo Medical University School of Medicine, South 1, West 16, Chuo-ku, Sapporo, 060-8543, Japan
| | - Masashi Idogawa
- Department of Medical Genome Sciences, Cancer Research Institute, Sapporo Medical University School of Medicine, South 1, West 17, Chuo-ku, Sapporo, 060-8556, Japan
| | - Takashi Tokino
- Department of Medical Genome Sciences, Cancer Research Institute, Sapporo Medical University School of Medicine, South 1, West 17, Chuo-ku, Sapporo, 060-8556, Japan
| | - Hisashi Uhara
- Department of Dermatology, Sapporo Medical University School of Medicine, South 1, West 16, Chuo-ku, Sapporo, 060-8543, Japan.
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Amarillo D, Flaherty KT, Sullivan RJ. Targeted Therapy Innovations for Melanoma. Hematol Oncol Clin North Am 2024; 38:973-995. [PMID: 38971651 DOI: 10.1016/j.hoc.2024.05.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/08/2024]
Abstract
Melanoma, a malignant tumor of melanocytes, poses a significant clinical challenge due to its aggressive nature and high potential for metastasis. The advent of targeted therapy has revolutionized the treatment landscape of melanoma, particularly for tumors harboring specific genetic alterations such as BRAF V600E mutations. Despite the initial success of targeted agents, resistance inevitably arises, underscoring the need for novel therapeutic strategies. This review explores the latest advances in targeted therapy for melanoma, focusing on new molecular targets, combination therapies, and strategies to overcome resistance.
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Affiliation(s)
- Dahiana Amarillo
- Oncóloga Médica, Departamento Básico de Medicina, Universidad de la República, Montevideo, Uruguay
| | - Keith T Flaherty
- Mass General Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
| | - Ryan J Sullivan
- Mass General Cancer Center, Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA
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Kim M, Shim HS, Kim S, Lee IH, Kim J, Yoon S, Kim HD, Park I, Jeong JH, Yoo C, Cheon J, Kim IH, Lee J, Hong SH, Park S, Jung HA, Kim JW, Kim HJ, Cha Y, Lim SM, Kim HS, Lee CK, Kim JH, Chun SH, Yun J, Park SY, Lee HS, Cho YM, Nam SJ, Na K, Yoon SO, Lee A, Jang KT, Yun H, Lee S, Kim JH, Kim WS. Clinical practice recommendations for the use of next-generation sequencing in patients with solid cancer: a joint report from KSMO and KSP. J Pathol Transl Med 2024; 58:147-164. [PMID: 39026440 PMCID: PMC11261170 DOI: 10.4132/jptm.2023.11.01] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Revised: 10/31/2023] [Accepted: 11/01/2023] [Indexed: 07/20/2024] Open
Abstract
In recent years, next-generation sequencing (NGS)-based genetic testing has become crucial in cancer care. While its primary objective is to identify actionable genetic alterations to guide treatment decisions, its scope has broadened to encompass aiding in pathological diagnosis and exploring resistance mechanisms. With the ongoing expansion in NGS application and reliance, a compelling necessity arises for expert consensus on its application in solid cancers. To address this demand, the forthcoming recommendations not only provide pragmatic guidance for the clinical use of NGS but also systematically classify actionable genes based on specific cancer types. Additionally, these recommendations will incorporate expert perspectives on crucial biomarkers, ensuring informed decisions regarding circulating tumor DNA panel testing.
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Affiliation(s)
- Miso Kim
- Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Hyo Sup Shim
- Department of Pathology, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Sheehyun Kim
- Department of Genomic Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - In Hee Lee
- Department of Oncology/Hematology, Kyungpook National University Chilgok Hospital, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Jihun Kim
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Shinkyo Yoon
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Hyung-Don Kim
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Inkeun Park
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Jae Ho Jeong
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Changhoon Yoo
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Jaekyung Cheon
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - In-Ho Kim
- Division of Medical Oncology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jieun Lee
- Division of Medical Oncology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Sook Hee Hong
- Division of Medical Oncology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Sehhoon Park
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hyun Ae Jung
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jin Won Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
| | - Han Jo Kim
- Division of Oncology and Hematology, Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Korea
| | - Yongjun Cha
- Division of Medical Oncology, Center for Colorectal Cancer, National Cancer Center, Goyang, Korea
| | - Sun Min Lim
- Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
| | - Han Sang Kim
- Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
| | - Choong-Kun Lee
- Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
| | - Jee Hung Kim
- Division of Medical Oncology, Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Sang Hoon Chun
- Division of Medical Oncology, Department of Internal Medicine, Bucheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jina Yun
- Division of Hematology/Oncology, Department of Medicine, Soonchunhyang University Bucheon Hospital, Bucheon, Korea
| | - So Yeon Park
- Department of Pathology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
| | - Hye Seung Lee
- Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Yong Mee Cho
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Soo Jeong Nam
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Kiyong Na
- Department of Pathology, Kyung Hee University Hospital, Kyung Hee University College of Medicine, Seoul, Korea
| | - Sun Och Yoon
- Department of Pathology, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Ahwon Lee
- Department of Hospital Pathology, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Kee-Taek Jang
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hongseok Yun
- Department of Genomic Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Sungyoung Lee
- Department of Genomic Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Jee Hyun Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
| | - Wan-Seop Kim
- Department of Pathology, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Korea
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Kim M, Shim HS, Kim S, Lee IH, Kim J, Yoon S, Kim HD, Park I, Jeong JH, Yoo C, Cheon J, Kim IH, Lee J, Hong SH, Park S, Jung HA, Kim JW, Kim HJ, Cha Y, Lim SM, Kim HS, Lee CK, Kim JH, Chun SH, Yun J, Park SY, Lee HS, Cho YM, Nam SJ, Na K, Yoon SO, Lee A, Jang KT, Yun H, Lee S, Kim JH, Kim WS. Clinical Practice Recommendations for the Use of Next-Generation Sequencing in Patients with Solid Cancer: A Joint Report from KSMO and KSP. Cancer Res Treat 2024; 56:721-742. [PMID: 38037319 PMCID: PMC11261187 DOI: 10.4143/crt.2023.1043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Accepted: 11/17/2023] [Indexed: 12/02/2023] Open
Abstract
In recent years, next-generation sequencing (NGS)-based genetic testing has become crucial in cancer care. While its primary objective is to identify actionable genetic alterations to guide treatment decisions, its scope has broadened to encompass aiding in pathological diagnosis and exploring resistance mechanisms. With the ongoing expansion in NGS application and reliance, a compelling necessity arises for expert consensus on its application in solid cancers. To address this demand, the forthcoming recommendations not only provide pragmatic guidance for the clinical use of NGS but also systematically classify actionable genes based on specific cancer types. Additionally, these recommendations will incorporate expert perspectives on crucial biomarkers, ensuring informed decisions regarding circulating tumor DNA panel testing.
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Affiliation(s)
- Miso Kim
- Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Hyo Sup Shim
- Department of Pathology, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Sheehyun Kim
- Department of Genomic Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - In Hee Lee
- Department of Oncology/Hematology, Kyungpook National University Chilgok Hospital, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Jihun Kim
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Shinkyo Yoon
- Department of Oncology,Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Hyung-Don Kim
- Department of Oncology,Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Inkeun Park
- Department of Oncology,Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Jae Ho Jeong
- Department of Oncology,Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Changhoon Yoo
- Department of Oncology,Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Jaekyung Cheon
- Department of Oncology,Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - In-Ho Kim
- Division of Medical Oncology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jieun Lee
- Division of Medical Oncology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Sook Hee Hong
- Division of Medical Oncology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Sehhoon Park
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hyun Ae Jung
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jin Won Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
| | - Han Jo Kim
- Division of Oncology and Hematology, Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Korea
| | - Yongjun Cha
- Division of Medical Oncology, Center for Colorectal Cancer, National Cancer Center, Goyang, Korea
| | - Sun Min Lim
- Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
| | - Han Sang Kim
- Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
| | - Choong-kun Lee
- Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
| | - Jee Hung Kim
- Division of Medical Oncology, Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Sang Hoon Chun
- Division of Medical Oncology, Department of Internal Medicine, Bucheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jina Yun
- Division of Hematology/Oncology, Department of Medicine, Soonchunhyang University Bucheon Hospital, Bucheon, Korea
| | - So Yeon Park
- Department of Pathology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
| | - Hye Seung Lee
- Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Yong Mee Cho
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Soo Jeong Nam
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Kiyong Na
- Department of Pathology, Kyung Hee University Hospital, Kyung Hee University College of Medicine, Seoul, Korea
| | - Sun Och Yoon
- Department of Pathology, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Ahwon Lee
- Department of Hospital Pathology, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Kee-Taek Jang
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hongseok Yun
- Department of Genomic Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Sungyoung Lee
- Department of Genomic Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Jee Hyun Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
| | - Wan-Seop Kim
- Department of Pathology, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Korea
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Takano Y, Shimokata T, Urakawa H, Kikumori T, Ando Y. Long-term response to MEK inhibitor monotherapy in a patient with papillary thyroid carcinoma harboring BRAF V600E mutation. Int Cancer Conf J 2024; 13:184-188. [PMID: 38962055 PMCID: PMC11217198 DOI: 10.1007/s13691-024-00670-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2024] [Accepted: 03/04/2024] [Indexed: 07/05/2024] Open
Abstract
Solid tumors harboring mutations in the Braf gene (BRAF) are currently treated by combination Braf/MEK inhibitor therapy, and there is an extensive literature on patient response rates. Alternatively, few studies have documented the clinical response of BRAF mutation-positive solid tumors to MEK inhibitor monotherapy. We report the case of a 57-year-old female diagnosed with papillary thyroid carcinoma and progressive lung metastases initially treated by total thyroidectomy and subsequent thyroid-stimulating hormone suppression therapy. Next-generation sequencing revealed that the tumor harbored a BRAF V600E mutation, and the patient was enrolled in a clinical study of the oral MEK1/2 inhibitor binimetinib. Shortly after starting treatment, the patient experienced pneumothorax due to rapid regression of lung metastases, and computed tomography after 6 months of binimetinib treatment revealed a partial sustained response. One year later, the dose was reduced because of an acneiform rash. After 5 years of binimetinib treatment, lung metastases had regrown, and treatment was switched to the oral multikinase inhibitor lenvatinib. This case demonstrates the potential of MEK inhibitor monotherapy as an alternative treatment for BRAF mutation-positive papillary thyroid carcinoma.
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Affiliation(s)
- Yuko Takano
- Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Nagoya, Japan
- Department of Breast and Endocrine Surgery, Nagoya University Hospital, Nagoya, Japan
| | - Tomoya Shimokata
- Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Nagoya, Japan
| | - Hiroshi Urakawa
- Department of Advanced Medicine, Nagoya University Hospital, Nagoya, Japan
| | - Toyone Kikumori
- Department of Breast and Endocrine Surgery, Nagoya University Hospital, Nagoya, Japan
| | - Yuichi Ando
- Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Nagoya, Japan
- Department of Advanced Medicine, Nagoya University Hospital, Nagoya, Japan
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10
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Desai A, Xiao AH, Choi D, Toruner MD, Walden D, Halfdanarson TR, Alberts S, McWilliams RR, Mahipal A, Ahn D, Babiker H, Stybayeva G, Revzin A, Kizilbash S, Adjei A, Bekaii-Saab T, Mansfield AS, Carr RM, Ma WW. Molecular Characterization and Therapeutic Opportunities in KRAS Wildtype Pancreatic Ductal Adenocarcinoma. Cancers (Basel) 2024; 16:1861. [PMID: 38791940 PMCID: PMC11119482 DOI: 10.3390/cancers16101861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2024] [Revised: 05/01/2024] [Accepted: 05/03/2024] [Indexed: 05/26/2024] Open
Abstract
PURPOSE To investigate the molecular characteristics of and potential for precision medicine in KRAS wildtype pancreatic ductal adenocarcinoma (PDAC). PATIENTS AND METHODS We investigated 27 patients with KRASWT PDAC at our institution. Clinical data were obtained via chart review. Tumor specimens for each subject were interrogated for somatic single nucleotide variants, insertion and deletions, and copy number variants by DNA sequencing. Gene fusions were detected from RNA-seq. A patient-derived organoid (PDO) was developed from a patient with a MET translocation and expanded ex vivo to predict therapeutic sensitivity prior to enrollment in a phase 2 clinical trial. RESULTS Transcriptomic analysis showed our cohort may be stratified by the relative gene expression of the KRAS signaling cascade. The PDO derived from our patient harboring a TFG-MET rearrangement was found to have in vitro sensitivity to the multi-tyrosine kinase inhibitor crizotinib. The patient was enrolled in the phase 2 SPARTA clinical trial and received monotherapy with vebrelitinib, a c-MET inhibitor, and achieved a partial and durable response. CONCLUSIONS KRASWT PDAC is molecularly distinct from KRASMUT and enriched with potentially actionable genetic variants. In our study, transcriptomic profiling revealed that the KRAS signaling cascade may play a key role in KRASWT PDAC. Our report of a KRASWT PDAC patient with TFG-MET rearrangement who responded to a cMET inhibitor further supports the pursuit of precision oncology in this sub-population. Identification of targetable mutations, perhaps through approaches like RNA-seq, can help enable precision-driven approaches to select optimal treatment based on tumor characteristics.
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Affiliation(s)
- Aakash Desai
- Department of Oncology, Mayo Clinic, Rochester, MN 55902, USA; (A.D.); (M.D.T.); (T.R.H.); (S.A.); (R.R.M.); (S.K.)
| | | | - Daheui Choi
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55902, USA; (D.C.); (G.S.); (A.R.)
| | - Merih D. Toruner
- Department of Oncology, Mayo Clinic, Rochester, MN 55902, USA; (A.D.); (M.D.T.); (T.R.H.); (S.A.); (R.R.M.); (S.K.)
| | - Daniel Walden
- Division of Hematology and Oncology, Mayo Clinic, Phoenix, AZ 85054, USA; (D.W.); (D.A.); (T.B.-S.)
| | - Thorvardur R. Halfdanarson
- Department of Oncology, Mayo Clinic, Rochester, MN 55902, USA; (A.D.); (M.D.T.); (T.R.H.); (S.A.); (R.R.M.); (S.K.)
| | - Steven Alberts
- Department of Oncology, Mayo Clinic, Rochester, MN 55902, USA; (A.D.); (M.D.T.); (T.R.H.); (S.A.); (R.R.M.); (S.K.)
| | - Robert R. McWilliams
- Department of Oncology, Mayo Clinic, Rochester, MN 55902, USA; (A.D.); (M.D.T.); (T.R.H.); (S.A.); (R.R.M.); (S.K.)
| | - Amit Mahipal
- Department of Oncology, University Hospitals Seidman Cancer Center, Cleveland, OH 44106, USA;
| | - Daniel Ahn
- Division of Hematology and Oncology, Mayo Clinic, Phoenix, AZ 85054, USA; (D.W.); (D.A.); (T.B.-S.)
| | - Hani Babiker
- Division of Hematology and Oncology, Mayo Clinic, Jacksonville, FL 32224, USA;
| | - Gulnaz Stybayeva
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55902, USA; (D.C.); (G.S.); (A.R.)
| | - Alexander Revzin
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55902, USA; (D.C.); (G.S.); (A.R.)
| | - Sani Kizilbash
- Department of Oncology, Mayo Clinic, Rochester, MN 55902, USA; (A.D.); (M.D.T.); (T.R.H.); (S.A.); (R.R.M.); (S.K.)
| | - Alex Adjei
- Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, USA;
| | - Tanios Bekaii-Saab
- Division of Hematology and Oncology, Mayo Clinic, Phoenix, AZ 85054, USA; (D.W.); (D.A.); (T.B.-S.)
| | - Aaron S. Mansfield
- Department of Oncology, Mayo Clinic, Rochester, MN 55902, USA; (A.D.); (M.D.T.); (T.R.H.); (S.A.); (R.R.M.); (S.K.)
| | - Ryan M. Carr
- Department of Oncology, Mayo Clinic, Rochester, MN 55902, USA; (A.D.); (M.D.T.); (T.R.H.); (S.A.); (R.R.M.); (S.K.)
| | - Wen Wee Ma
- Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, USA;
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11
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Nishio J, Nakayama S, Aoki M. Recent Advances in the Diagnosis, Pathogenesis, and Management of Myxoinflammatory Fibroblastic Sarcoma. Int J Mol Sci 2024; 25:1127. [PMID: 38256198 PMCID: PMC10816835 DOI: 10.3390/ijms25021127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Revised: 01/12/2024] [Accepted: 01/16/2024] [Indexed: 01/24/2024] Open
Abstract
Myxoinflammatory fibroblastic sarcoma (MIFS) is an infiltrative, locally aggressive fibroblastic neoplasm of intermediate malignancy that typically arises in the distal extremities of middle-aged adults. It can histologically be confused with a number of benign and malignant conditions. Recently, high-grade examples of MIFS have been described. Immunohistochemistry plays a very limited role in the diagnosis of MIFS. Several genetic alterations have been identified in MIFS, including a t(1;10)(p22;q24) translocation with TGFBR3 and/or OGA rearrangements, BRAF rearrangement, and VGLL3 amplification. Although it appears that VGLL3 amplification is the most consistent alteration, the molecular pathogenesis of MIFS remains poorly understood. A wide resection is considered the standard treatment for MIFS. Radiotherapy may be a viable option in cases with inadequate surgical margins or cases where surgery is likely to cause significant functional impairment. The systemic treatment options for advanced or metastatic disease are very limited. This review provides an updated overview of the clinicoradiological features, pathogenesis, histopathology, and treatment of MIFS.
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Affiliation(s)
- Jun Nishio
- Section of Orthopaedic Surgery, Department of Medicine, Fukuoka Dental College, 2-15-1 Tamura, Sawara-ku, Fukuoka 814-0193, Japan
| | - Shizuhide Nakayama
- Department of Orthopaedic Surgery, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan;
| | - Mikiko Aoki
- Department of Pathology, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan;
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12
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Fernandez MF, Choi J, Sosman J. New Approaches to Targeted Therapy in Melanoma. Cancers (Basel) 2023; 15:3224. [PMID: 37370834 PMCID: PMC10296143 DOI: 10.3390/cancers15123224] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Revised: 06/13/2023] [Accepted: 06/15/2023] [Indexed: 06/29/2023] Open
Abstract
It was just slightly more than a decade ago when metastatic melanoma carried a dismal prognosis with few, if any, effective therapies. Since then, the evolution of cancer immunotherapy has led to new and effective treatment approaches for melanoma. However, despite these advances, a sizable portion of patients with advanced melanoma have de novo or acquired resistance to immune checkpoint inhibitors. At the same time, therapies (BRAF plus MEK inhibitors) targeting the BRAFV600 mutations found in 40-50% of cutaneous melanomas have also been critical for optimizing management and improving patient outcomes. Even though immunotherapy has been established as the initial therapy in most patients with cutaneous melanoma, subsequent effective therapy is limited to BRAFV600 melanoma. For all other melanoma patients, driver mutations have not been effectively targeted. Numerous efforts are underway to target melanomas with NRAS mutations, NF-1 LOF mutations, and other genetic alterations leading to activation of the MAP kinase pathway. In this era of personalized medicine, we will review the current genetic landscape, molecular classifications, emerging drug targets, and the potential for combination therapies for non-BRAFV600 melanoma.
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Affiliation(s)
| | | | - Jeffrey Sosman
- Robert H. Lurie Comprehensive Cancer Center, Division of Hematology/Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; (M.F.F.); (J.C.)
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13
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Roy SF, Milante R, Pissaloux D, Tirode F, Bastian BC, Fouchardière ADL, Yeh I. Spectrum of Melanocytic Tumors Harboring BRAF Gene Fusions: 58 Cases With Histomorphologic and Genetic Correlations. Mod Pathol 2023; 36:100149. [PMID: 36841436 DOI: 10.1016/j.modpat.2023.100149] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Revised: 02/08/2023] [Accepted: 02/16/2023] [Indexed: 02/27/2023]
Abstract
We report a series of 58 melanocytic tumors that harbor an activating fusion of BRAF, a component of the mitogen-activated protein kinase (MAPK) signaling cascade. Cases were diagnosed as melanocytic nevus (n = 12, 21%), diagnostically ambiguous favor benign (n = 22, 38%), and diagnostically ambiguous concerning for melanoma (n = 12, 21%) or melanoma (n = 12, 21%). Three main histopathologic patterns were observed. The first pattern (buckshot fibrosis) was characterized by large, epithelioid melanocytes arrayed as single cells or "buckshot" within marked stromal desmoplasia. The second pattern (cords in whorled fibrosis) demonstrated polypoid growth with a whorled arrangement of cords and single melanocytes within desmoplasia. The third pattern (spindle-cell fascicles) showed fascicular growth of spindled melanocytes. Cytomorphologic features characteristic of Spitz nevi were observed in most cases (n = 50, 86%). Most of the cases (n = 54, or 93%) showed stromal desmoplasia. Histomorphology alone was not sufficient in distinguishing benign from malignant melanocytic tumors with BRAF fusion gene because the only histopathologic features more commonly associated with a diagnosis of malignancy included dermal mitoses (P = .046) and transepidermal elimination of melanocytes (P = .013). BRAF fusion kinases are targetable by kinase inhibitors and, thus, should be considered as relevant genetic alterations in the molecular workup of melanomas. Recognizing the 3 main histopathologic patterns of melanocytic tumors with BRAF fusion gene will aid in directing ancillary testing.
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Affiliation(s)
- Simon F Roy
- Department of Dermatology, Yale School of Medicine, New Haven, Connecticut
| | - Riza Milante
- Department of Dermatology, University of California in San Francisco, San Francisco, California
| | - Daniel Pissaloux
- Department of Biopathology, Centre Léon Bérard, Lyon, France; University of Lyon, Université Claude Bernard Lyon 1, CNRS UMR 5286, INSERM U1052, Cancer Research Centre of Lyon, Lyon, France
| | - Franck Tirode
- University of Lyon, Université Claude Bernard Lyon 1, CNRS UMR 5286, INSERM U1052, Cancer Research Centre of Lyon, Lyon, France
| | - Boris C Bastian
- Department of Dermatology, University of California in San Francisco, San Francisco, California; Department of Pathology, University of California in San Francisco, San Francisco, California
| | - Arnaud de la Fouchardière
- Department of Biopathology, Centre Léon Bérard, Lyon, France; University of Lyon, Université Claude Bernard Lyon 1, CNRS UMR 5286, INSERM U1052, Cancer Research Centre of Lyon, Lyon, France
| | - Iwei Yeh
- Department of Dermatology, University of California in San Francisco, San Francisco, California; Department of Pathology, University of California in San Francisco, San Francisco, California.
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14
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Hagstrom M, Fumero-Velázquez M, Dhillon S, Olivares S, Gerami P. An update on genomic aberrations in Spitz naevi and tumours. Pathology 2023; 55:196-205. [PMID: 36631338 DOI: 10.1016/j.pathol.2022.12.001] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 11/28/2022] [Accepted: 12/05/2022] [Indexed: 12/24/2022]
Abstract
Spitz neoplasms continue to be a diagnostic challenge for dermatopathologists and are defined by distinctive morphological and genetic features. With the recent advancements in genomic sequencing, the classification, diagnosis, and prognostication of these tumours have greatly improved. Several subtypes of Spitz neoplasms have been identified based on their specific genomic aberrations, which often correlate with distinctive morphologies and biological behaviour. These genetic driver events can be classified into four major groups, including: (1) mutations [HRAS mutations (with or without 11p amplification) and 6q23 deletions]; (2) tyrosine kinase fusions (ROS1, ALK, NTRK1-3, MET and RET); (3) serine/threonine kinase fusions and mutations (BRAF, MAP3K8, and MAP2K1); and (4) other rare genomic aberrations. These driver genomic events are hypothesised to enable the initial proliferation of melanocytes and are often accompanied by additional genomic aberrations that affect biological behaviour. The discovery of theses genomic fusions has allowed for a more objective definition of a Spitz neoplasm. Further studies have shown that the majority of morphologically Spitzoid appearing melanocytic neoplasms with aggressive behaviour are in fact BRAF or NRAS mutated tumours mimicking Spitz. Truly malignant fusion driven Spitz neoplasms may occur but are relatively uncommon, and biomarkers such as homozygous 9p21 (CDKN2A) deletions or TERT-p mutations can have some prognostic value in such cases. In this review, we discuss the importance and various methods of identifying Spitz associated genomic fusions to help provide more definitive classification. We also discuss characteristic features of the various fusion subtypes as well as prognostic biomarkers.
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Affiliation(s)
- Michael Hagstrom
- Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Mónica Fumero-Velázquez
- Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Soneet Dhillon
- Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Shantel Olivares
- Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Pedram Gerami
- Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
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15
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Khan S, Martinez-Ledesma E, Dong J, Mahalingam R, Park SY, Piao Y, Koul D, Balasubramaniyan V, de Groot JF, Yung WKA. Neuronal differentiation drives the antitumor activity of mitogen-activated protein kinase kinase (MEK) inhibition in glioblastoma. Neurooncol Adv 2023; 5:vdad132. [PMID: 38130900 PMCID: PMC10734674 DOI: 10.1093/noajnl/vdad132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2023] Open
Abstract
Background Epidermal growth factor receptor (EGFR) amplification is found in nearly 40%-50% of glioblastoma cases. Several EGFR inhibitors have been tested in glioblastoma but have failed to demonstrate long-term therapeutic benefit, presumably because of acquired resistance. Targeting EGFR downstream signaling with mitogen-activated protein kinase kinase 1 and 2 (MEK1/2) inhibitors would be a more effective approach to glioblastoma treatment. We tested the therapeutic potential of MEK1/2 inhibitors in glioblastoma using 3D cultures of glioma stem-like cells (GSCs) and mouse models of glioblastoma. Methods Several MEK inhibitors were screened in an unbiased high-throughput platform using GSCs. Cell death was evaluated using flow cytometry and Western blotting (WB) analysis. RNA-seq, real-time quantitative polymerase chain reaction, immunofluorescence, and WB analysis were used to identify and validate neuronal differentiation. Results Unbiased screening of multiple MEK inhibitors in GSCs showed antiproliferative and apoptotic cell death in sensitive cell lines. An RNA-seq analysis of cells treated with trametinib, a potent MEK inhibitor, revealed upregulation of neurogenesis and neuronal differentiation genes, such as achaete-scute homolog 1 (ASCL1), delta-like 3 (DLL3), and neurogenic differentiation 4 (NeuroD4). We validated the neuronal differentiation phenotypes in vitro and in vivo using selected differentiation markers (β-III-tubulin, ASCL1, DLL3, and NeuroD4). Oral treatment with trametinib in an orthotopic GSC xenograft model significantly improved animal survival, with 25%-30% of mice being long-term survivors. Conclusions Our findings demonstrated that MEK1/2 inhibition promotes neuronal differentiation in glioblastoma, a potential additional mechanism of action of MEK1/2 inhibitors. Thus, MEK inhibitors could be efficacious in glioblastoma patients with activated EGFR/MAPK signaling.
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Affiliation(s)
- Sabbir Khan
- Department of Neuro-Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Emmanuel Martinez-Ledesma
- Department of Neuro-Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey, Nuevo León, Mexico
- Tecnologico de Monterrey, Institute for Obesity Research, Monterrey, Nuevo León, Mexico
| | - Jianwen Dong
- Department of Neuro-Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Rajasekaran Mahalingam
- Department of Symptom Research, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Soon Young Park
- Department of Neuro-Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Yuji Piao
- Department of Neuro-Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Dimpy Koul
- Department of Neuro-Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | | | - John F de Groot
- Department of Neuro-Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
- Department of Neurosurgery, University of California-San Francisco, San Francisco, California, USA
| | - W K Alfred Yung
- Department of Neuro-Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
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16
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Lee CL, Holter S, Borgida A, Dodd A, Ramotar S, Grant R, Wasson K, Elimova E, Jang RW, Moore M, Kim TK, Khalili K, Moulton CA, Gallinger S, O’Kane GM, Knox JJ. Germline BRCA2 variants in advanced pancreatic acinar cell carcinoma: A case report and review of literature. World J Gastroenterol 2022; 28:6421-6432. [PMID: 36533108 PMCID: PMC9753052 DOI: 10.3748/wjg.v28.i45.6421] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2022] [Revised: 11/02/2022] [Accepted: 11/16/2022] [Indexed: 12/02/2022] Open
Abstract
BACKGROUND Pancreatic acinar cell carcinoma (PACC) is a rare tumor. Up to 45% of PACCs have alterations in the DNA damage repair pathway and 23% harbor rearrangements in the BRAF or RAF1 genes. We present a PACC case with a germline BRCA2 likely pathogenic variant (LPV) to highlight the impact of genomic testing on treatment decisions and patient outcomes. In our larger case series, we provide clinic-based information on additional 10 PACC patients treated in our center.
CASE SUMMARY A 70-year-old male was diagnosed with advanced PACC. At presentation, he was cachectic with severe arthralgia despite prednisolone and a skin rash that was later confirmed to be panniculitis. He was treated with modified FOLFIRINOX (mFFX) with the knowledge of the germline BRCA2 LPV. Following 11 cycles of mFFX, a computed tomography (CT) scan demonstrated significant tumor response in the pancreatic primary and hepatic metastases, totaling 70% from baseline as per Response Evaluation Criteria in Solid Tumors. Resolution of the skin panniculitis was also noted. We identified two additional PACCs with druggable targets in our case series. Our data contribute to practical evidence for the value of germline and somatic profiling in the management of rare diseases like PACC.
CONCLUSION This patient and others in our larger case series highlight the importance of genomic testing in PACC with potential utility in personalized treatment.
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Affiliation(s)
- Cha Len Lee
- Division of Medical Oncology and Hematology, Wallace McCain Center for Pancreatic Cancer, Princess Margaret Cancer Centre, Toronto M5G1Z5, ON, Canada
| | - Spring Holter
- Division of Medical Oncology and Hematology, Wallace McCain Center for Pancreatic Cancer, Princess Margaret Cancer Centre, Toronto M5G1Z5, ON, Canada
| | - Ayelet Borgida
- Division of Medical Oncology and Hematology, Wallace McCain Center for Pancreatic Cancer, Princess Margaret Cancer Centre, Toronto M5G1Z5, ON, Canada
| | - Anna Dodd
- Division of Medical Oncology and Hematology, Wallace McCain Center for Pancreatic Cancer, Princess Margaret Cancer Centre, Toronto M5G1Z5, ON, Canada
| | - Stephanie Ramotar
- Division of Medical Oncology and Hematology, Wallace McCain Center for Pancreatic Cancer, Princess Margaret Cancer Centre, Toronto M5G1Z5, ON, Canada
| | - Robert Grant
- Division of Medical Oncology and Hematology, Wallace McCain Center for Pancreatic Cancer, Princess Margaret Cancer Centre, Toronto M5G1Z5, ON, Canada
| | - Kristy Wasson
- Division of Medical Oncology and Hematology, Wallace McCain Center for Pancreatic Cancer, Princess Margaret Cancer Centre, Toronto M5G1Z5, ON, Canada
| | - Elena Elimova
- Division of Medical Oncology and Hematology, Wallace McCain Center for Pancreatic Cancer, Princess Margaret Cancer Centre, Toronto M5G1Z5, ON, Canada
| | - Raymond W Jang
- Division of Medical Oncology and Hematology, Wallace McCain Center for Pancreatic Cancer, Princess Margaret Cancer Centre, Toronto M5G1Z5, ON, Canada
| | - Malcolm Moore
- Division of Medical Oncology and Hematology, Wallace McCain Center for Pancreatic Cancer, Princess Margaret Cancer Centre, Toronto M5G1Z5, ON, Canada
| | - Tae Kyoung Kim
- Department of Medical Imaging, Wallace McCain Center for Pancreatic Cancer, Princess Margaret Cancer Centre, Toronto M5G1Z5, ON, Canada
| | - Korosh Khalili
- Department of Medical Imaging, Wallace McCain Center for Pancreatic Cancer, Princess Margaret Cancer Centre, Toronto M5G1Z5, ON, Canada
| | - Carol-Anne Moulton
- Hepatobiliary/Pancreatic Surgical Program, Wallace McCain Center for Pancreatic Cancer, Princess Margaret Cancer Centre, Toronto M5G1Z5, ON, Canada
| | - Steven Gallinger
- Hepatobiliary/Pancreatic Surgical Program, Wallace McCain Center for Pancreatic Cancer, Princess Margaret Cancer Centre, Toronto M5G1Z5, ON, Canada
| | - Grainne M O’Kane
- Division of Medical Oncology and Hematology, Wallace McCain Center for Pancreatic Cancer, Princess Margaret Cancer Centre, Toronto M5G1Z5, ON, Canada
| | - Jennifer J Knox
- Division of Medical Oncology and Hematology, Wallace McCain Center for Pancreatic Cancer, Princess Margaret Cancer Centre, Toronto M5G1Z5, ON, Canada
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17
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Chen R, Li J, Fujimoto J, Hong L, Hu X, Quek K, Tang M, Mitra A, Behrens C, Chow CW, Jiang P, Little LD, Gumbs C, Song X, Zhang J, Tan D, Heymach JV, Wistuba I, Futreal PA, Gibbons DL, Byers LA, Zhang J, Reuben A. Immunogenomic intertumor heterogeneity across primary and metastatic sites in a patient with lung adenocarcinoma. J Exp Clin Cancer Res 2022; 41:172. [PMID: 35546239 PMCID: PMC9092788 DOI: 10.1186/s13046-022-02361-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Accepted: 04/10/2022] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Lung cancer is the leading cause of cancer death, partially owing to its extensive heterogeneity. The analysis of intertumor heterogeneity has been limited by an inability to concurrently obtain tissue from synchronous metastases unaltered by multiple prior lines of therapy.
Methods
In order to study the relationship between genomic, epigenomic and T cell repertoire heterogeneity in a rare autopsy case from a 32-year-old female never-smoker with left lung primary late-stage lung adenocarcinoma (LUAD), we did whole-exome sequencing (WES), DNA methylation and T cell receptor (TCR) sequencing to characterize the immunogenomic landscape of one primary and 19 synchronous metastatic tumors.
Results
We observed heterogeneous mutation, methylation, and T cell patterns across distinct metastases. Only TP53 mutation was detected in all tumors suggesting an early event while other cancer gene mutations were later events which may have followed subclonal diversification. A set of prevalent T cell clonotypes were completely excluded from left-side thoracic tumors indicating distinct T cell repertoire profiles between left-side and non left-side thoracic tumors. Though a limited number of predicted neoantigens were shared, these were associated with homology of the T cell repertoire across metastases. Lastly, ratio of methylated neoantigen coding mutations was negatively associated with T-cell density, richness and clonality, suggesting neoantigen methylation may partially drive immunosuppression.
Conclusions
Our study demonstrates heterogeneous genomic and T cell profiles across synchronous metastases and how restriction of unique T cell clonotypes within an individual may differentially shape the genomic and epigenomic landscapes of synchronous lung metastases.
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Abstract
PURPOSE OF REVIEW Immune checkpoint inhibitors (ICIs) have revolutionized the treatment paradigm for patients with metastatic melanoma; however, there remains an unmet clinical need for alternative treatment options for those patients who are either intolerant or refractory to immunotherapy. Here we review the role and clinical efficacy of targeted therapies for BRAFV600 wild-type melanoma. RECENT FINDINGS Genomic analyses in BRAFV600 wild-type melanoma have previously identified driver mutations along the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3K)-AKT pathways that can be targeted with small molecule inhibitors. New drugs such as bispecific antibodies and antibody drug conjugates may have significant clinical activity even in rare subtypes of melanoma that are less responsive to ICIs. Historically, molecular-targeted therapies have modest clinical success in treating BRAFV600 wild-type melanoma; nevertheless, they may have a significant clinical role in select, genetically distinct groups of patients. Next-generation immunotherapies or immunomodulators may represent the latest breakthrough in the treatment of melanoma. Additional studies are needed to identify novel drug targets and synergistic drug combinations to expand treatment options and optimize clinical outcomes.
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Moran JMT, Le LP, Nardi V, Golas J, Farahani AA, Signorelli S, Onozato ML, Foreman RK, Duncan LM, Lawrence DP, Lennerz JK, Dias-Santagata D, Hoang MP. Identification of fusions with potential clinical significance in melanoma. Mod Pathol 2022; 35:1837-1847. [PMID: 35871080 DOI: 10.1038/s41379-022-01138-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Revised: 07/01/2022] [Accepted: 07/04/2022] [Indexed: 12/24/2022]
Abstract
Though uncommon in melanoma, gene fusions may have therapeutic implications. Next generation sequencing-based clinical assays, designed to detect relevant gene fusions, mutations, and copy number changes, were performed on 750 melanomas (375 primary and 375 metastases) at our institution from 2014-2021. These included 599 (80%) cutaneous, 38 (5%) acral, 11 (1.5%) anorectal, 23 (3%) sinonasal, 27 (3.6%) eye (uveal/ conjunctiva), 11 (1.5%) genital (vulva/penile), and 41 (5.5%) melanomas of unknown primary. Sixteen fusions (2%) were detected in samples from 16 patients: 12/599 (2%) cutaneous, 2/38 (5%) acral, 1/9 (11%) vulva, 1/23(4.3%) sinonasal; and 12/16 (75%) fusions were potentially targetable. We identified two novel rearrangements: NAGS::MAST2 and NOTCH1::GNB1; and two fusions that have been reported in other malignancies but not in melanoma: CANT1::ETV4 (prostate cancer) and CCDC6::RET (thyroid cancer). Additional fusions, previously reported in melanoma, included: EML4::ALK, MLPH::ALK, AGAP3::BRAF, AGK::BRAF, CDH3::BRAF, CCT8::BRAF, DIP2B::BRAF, EFNB1::RAF1, LRCH3::RAF1, MAP4::RAF1, RUFY1::RAF1, and ADCY2::TERT. Fusion positive melanomas harbored recurrent alterations in TERT and CDKN2A, among others. Gene fusions were exceedingly rare (0.2%) in BRAF/RAS/NF1-mutant tumors and were detected in 5.6% of triple wild-type melanomas. Interestingly, gene rearrangements were significantly enriched within the subset of triple wild-type melanomas that harbor TERT promoter mutations (18% versus 2%, p < 0.0001). Thirteen (81%) patients were treated with immunotherapy for metastatic disease or in the adjuvant setting. Six of 12 (50%) patients with potentially actionable fusions progressed on immunotherapy, and 3/6 (50%) were treated with targeted agents (ALK and MEK inhibitors), 2 off-label and 1 as part of a clinical trial. One patient with an AGAP3::BRAF fusion positive melanoma experienced a 30-month long response to trametinib. We show that, detecting fusions, especially in triple wild-type melanomas with TERT promoter mutations, may have a clinically significant impact in patients with advanced disease who have failed front-line immunotherapy.
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Affiliation(s)
- Jakob M T Moran
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Long P Le
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Valentina Nardi
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Josephine Golas
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Alexander A Farahani
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Sylvia Signorelli
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Maristela L Onozato
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Ruth K Foreman
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Lyn M Duncan
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Donald P Lawrence
- Division of Medical Oncology, Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA
| | - Jochen K Lennerz
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Dora Dias-Santagata
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
| | - Mai P Hoang
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
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20
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Girod M, Dalle S, Mortier L, Dalac S, Leccia MT, Dutriaux C, Montaudié H, de Quatrebarbes J, Lesimple T, Brunet-Possenti F, Saiag P, Maubec E, Legoupil D, Stoebner PE, Arnault JP, Lefevre W, Lebbe C, Dereure O. Non-V600E/K BRAF Mutations in Metastatic Melanoma: Molecular Description, Frequency, and Effectiveness of Targeted Therapy in a Large National Cohort. JCO Precis Oncol 2022; 6:e2200075. [DOI: 10.1200/po.22.00075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
PURPOSE Mitogen-activating protein kinase inhibitors (MAPKis) are largely used in V600E/K BRAF–mutated metastatic melanomas, but data regarding effectiveness of targeted therapy in patients with rare BRAF mutations and molecular description of these infrequent mutations are scarce. PATIENTS AND METHODS A multicenter study was conducted on patients with metastatic melanoma harboring a well-identified mutation of BRAF and enrolled from March 2013 to June 2021 in the French nationwide prospective cohort MelBase. The molecular BRAF mutation pattern, response to MAPKis when applicable, and survival data were analyzed. RESULTS Of 856 selected patients, 51 (6%) harbored a non-V600E/K BRAF mutation involving codons V600 (24 of 51, 47%; V600G 27.4%, V600R 15.6%), K601 (6 of 51, 11.7%), and L597 (4 of 51, 7.8%). An objective response to MAPKis either BRAF inhibitor (BRAFi) alone or combined with MEK inhibitor was achieved in 56% (353 of 631) of V600E/K, 58% (11 of 19) of non-E/K V600, and 22% (2 of 9) of non-V600 BRAF-mutated patients, with a median progression-free survival of 7.7, 7.8, and 2.8 months, respectively. Overall, objective response rate was higher with BRAFi + MEK inhibitor combination than with BRAFi in monotherapy for each subset. CONCLUSION Rare BRAF mutations are not anecdotal in the metastatic melanoma population. Although data interpretation must remain careful owing to the limited size of some subsets of patients, non-E/K V600 BRAF mutations seem to confer a high sensitivity to targeted therapy, whereas MAPKis seem less effective in patients with non-V600 BRAF mutations. However, this strategy may be used as an alternative option in the case of immunotherapy failure in the latter population.
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Affiliation(s)
- Manon Girod
- Department of Dermatology, University of Montpellier, Montpellier, France
| | - Stéphane Dalle
- Department of Dermatology, Service de dermatologie, Hôpital Lyon Sud, Centre de recherche en cancérologie de Lyon, Université Claude Bernard Lyon 1, Hospices Civils de Lyon, Lyon, France
| | | | - Sophie Dalac
- Department of Dermatology, Hôpital du bocage, Dijon, France
| | | | - Caroline Dutriaux
- Department of Dermatology, Centre Hospitalier Universitaire, Bordeaux, France
| | - Henri Montaudié
- Department of Dermatology, University Hospital of Nice, Université Côte d'Azur and INSERM U1065, Centre Méditerranéen de Médecine Moléculaire, Université Côte d'Azur, Nice, France
| | | | - Thierry Lesimple
- Department of Medical Oncology, Centre Régional de Lutte contre le Cancer Eugène Marquis, Rennes, France
| | | | - Philippe Saiag
- Department of General and Oncologic Dermatology, Ambroise-Paré Hospital, APHP & EA3440 "Biomarkers in Cancerology and Hemato-Oncology”, UVSQ, Université Paris-Saclay, Boulogne-Billancourt, France
| | - Eve Maubec
- Department of Dermatology, Hôpital Avicenne, Bobigny, France
| | - Delphine Legoupil
- Department of Dermatology, Centre Hospitalier Universitaire, Brest, France
| | | | | | - Wendy Lefevre
- Department of Dermatology, MelBase, Hôpital Saint-Louis, Paris, France
| | - Celeste Lebbe
- Department of Dermatology, DMU ICARE, AP-HP Hôpital Saint Louis and INSERM U976, Université de Paris, Paris, France
| | - Olivier Dereure
- Department of Dermatology, University of Montpellier, Montpellier, France
- INSERM U1058 Pathogenesis and Control of Chronic and Emerging Infections, University of Montpellier, Montpellier, France
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21
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Clark HE, Huang YYM, Vance GH, Alomari AK. Fatal melanoma with a novel MYO5A-BRAF fusion and small associated conventional nevus: A case report and review of literature. J Cutan Pathol 2022; 49:808-812. [PMID: 35596628 PMCID: PMC9545590 DOI: 10.1111/cup.14263] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2021] [Revised: 05/17/2022] [Accepted: 05/19/2022] [Indexed: 12/01/2022]
Abstract
Kinase fusions play an important role in the pathogenesis of Spitz neoplasms and occasionally non-Spitz neoplasms. We report a case of a 19-year-old woman with a growing nodule on the scalp, morphologically consistent with a diagnosis of melanoma with epithelioid features arising in association with small nevus. This tumor aggressively metastasized and failed to respond to immunotherapy. Next-generation sequencing of a metastatic focus revealed an MYO5A-BRAF kinase fusion with a low mutational burden and fluorescence in situ hybridization (FISH) of the primary melanoma showed similar results. FISH testing of the associated nevus failed because of technical reasons. MYO5A has rarely been reported as the fusion partner with BRAF-rearranged melanocytic tumors. Moreover, this case raises speculations and contributes to the growing literature on the pathogenesis, nomenclature, and tumorigenic pathways in kinase-fusion melanomas. The patient succumbed to disease, which is in concordance with some literature suggesting aggressive behavior of BRAF fusion melanomas with TERT promoter mutations.
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Affiliation(s)
| | - Yuan Yu Michael Huang
- Department of DermatologyIndiana University School of MedicineIndianapolisIndianaUSA
| | - Gail H. Vance
- Department of Pathology and Laboratory MedicineIndiana University School of MedicineIndianapolisIndianaUSA,Department of Medical and Molecular GeneticsIndiana University School of MedicineIndianapolisIndianaUSA
| | - Ahmed K. Alomari
- Department of DermatologyIndiana University School of MedicineIndianapolisIndianaUSA,Department of Pathology and Laboratory MedicineIndiana University School of MedicineIndianapolisIndianaUSA
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22
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Fenor MD, Ruiz-Llorente S, Rodríguez-Moreno JF, Caleiras E, Torrego JC, Sevillano-Fernández E, Navarro P, Yagüe-Fernández M, Amarilla-Quintana S, Barquín A, García-Donas J. MEK inhibitor sensitivity in BRAF fusion-driven prostate cancer. CLINICAL & TRANSLATIONAL ONCOLOGY : OFFICIAL PUBLICATION OF THE FEDERATION OF SPANISH ONCOLOGY SOCIETIES AND OF THE NATIONAL CANCER INSTITUTE OF MEXICO 2022; 24:2432-2440. [PMID: 35994225 DOI: 10.1007/s12094-022-02916-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Accepted: 07/27/2022] [Indexed: 11/25/2022]
Abstract
PURPOSE The identification of subpopulations harboring druggable targets has become a major step forward in the subclassification of solid tumors into small groups suitable for specific therapies. BRAF fusions represent a paradigm of uncommon and targetable oncogenic events and have been widely correlated to the development of specific malignancies. However, they are only present in a limited frequency across most common tumor types. At this regard, we performed a genomic screening aimed to identifying rare variants associated to advanced prostate cancer development. METHODS Tumoral tissue genomic screening of 41 patients developing advanced prostate cancer was performed at our center as part of the GETHI XX study. The project, sponsored by the Spanish Collaborative Group in Rare Cancers (GETHI), aims to analyze the molecular background of rare tumors and to discover unfrequent molecular variants in common tumors. RESULTS Here we present the clinical outcome and an in-deep molecular analysis performed in a case harboring a SND1-BRAF fusion gene. The identification of such rearrangement in a patient refractory to standard therapies led to the administration of trametinib (MEK inhibitor). Despite unsensitive to standard therapies, the patient achieved a dramatic response to trametinib. A comprehensive study of the tumor demonstrated this event to be a trunk alteration with higher expression of MEK in areas of tumor invasion. CONCLUSIONS Our study describes the patient-driven discovery of the first BRAF fusion-driven prostate cancer effectively treated with trametinib. Consequently, MAPK pathway activation could define a new subtype of prostate cancer susceptible to a tailored management.
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Affiliation(s)
- María Dolores Fenor
- Laboratory of Innovation in Oncology, HM CIOCC MADRID (Centro Integral Oncológico Clara Campal), Hospital Universitario HM Sanchinarro, HM Hospitales, Madrid, Spain
- Department of Genitourinary and Gynecological Tumors, Hospital Universitario HM Sanchinarro, HM Hospitales, Madrid, Spain
| | - Sergio Ruiz-Llorente
- Laboratory of Innovation in Oncology, HM CIOCC MADRID (Centro Integral Oncológico Clara Campal), Hospital Universitario HM Sanchinarro, HM Hospitales, Madrid, Spain
- Department of Genitourinary and Gynecological Tumors, Hospital Universitario HM Sanchinarro, HM Hospitales, Madrid, Spain
- Institute of Applied Molecular Medicine (IMMA), Department of Basic Medical Sciences, Facultad de Medicina, Universidad San Pablo CEU, CEU Universities, Urbanización Montepríncipe, Monteprincipe Avenue, 28668, Madrid, Spain
| | - Juan Francisco Rodríguez-Moreno
- Laboratory of Innovation in Oncology, HM CIOCC MADRID (Centro Integral Oncológico Clara Campal), Hospital Universitario HM Sanchinarro, HM Hospitales, Madrid, Spain
- Department of Genitourinary and Gynecological Tumors, Hospital Universitario HM Sanchinarro, HM Hospitales, Madrid, Spain
- Institute of Applied Molecular Medicine (IMMA), Department of Basic Medical Sciences, Facultad de Medicina, Universidad San Pablo CEU, CEU Universities, Urbanización Montepríncipe, Monteprincipe Avenue, 28668, Madrid, Spain
| | - Eduardo Caleiras
- Histopathology Core Unit, Spanish National Cancer Center (CNIO), Madrid, Spain
| | | | - Elena Sevillano-Fernández
- Laboratory of Innovation in Oncology, HM CIOCC MADRID (Centro Integral Oncológico Clara Campal), Hospital Universitario HM Sanchinarro, HM Hospitales, Madrid, Spain
- Department of Genitourinary and Gynecological Tumors, Hospital Universitario HM Sanchinarro, HM Hospitales, Madrid, Spain
- Institute of Applied Molecular Medicine (IMMA), Department of Basic Medical Sciences, Facultad de Medicina, Universidad San Pablo CEU, CEU Universities, Urbanización Montepríncipe, Monteprincipe Avenue, 28668, Madrid, Spain
| | - Paloma Navarro
- Laboratory of Innovation in Oncology, HM CIOCC MADRID (Centro Integral Oncológico Clara Campal), Hospital Universitario HM Sanchinarro, HM Hospitales, Madrid, Spain
- Department of Genitourinary and Gynecological Tumors, Hospital Universitario HM Sanchinarro, HM Hospitales, Madrid, Spain
- Institute of Applied Molecular Medicine (IMMA), Department of Basic Medical Sciences, Facultad de Medicina, Universidad San Pablo CEU, CEU Universities, Urbanización Montepríncipe, Monteprincipe Avenue, 28668, Madrid, Spain
| | - Mónica Yagüe-Fernández
- Laboratory of Innovation in Oncology, HM CIOCC MADRID (Centro Integral Oncológico Clara Campal), Hospital Universitario HM Sanchinarro, HM Hospitales, Madrid, Spain
- Department of Genitourinary and Gynecological Tumors, Hospital Universitario HM Sanchinarro, HM Hospitales, Madrid, Spain
- Institute of Applied Molecular Medicine (IMMA), Department of Basic Medical Sciences, Facultad de Medicina, Universidad San Pablo CEU, CEU Universities, Urbanización Montepríncipe, Monteprincipe Avenue, 28668, Madrid, Spain
| | - Sandra Amarilla-Quintana
- Laboratory of Innovation in Oncology, HM CIOCC MADRID (Centro Integral Oncológico Clara Campal), Hospital Universitario HM Sanchinarro, HM Hospitales, Madrid, Spain
- Department of Genitourinary and Gynecological Tumors, Hospital Universitario HM Sanchinarro, HM Hospitales, Madrid, Spain
- Institute of Applied Molecular Medicine (IMMA), Department of Basic Medical Sciences, Facultad de Medicina, Universidad San Pablo CEU, CEU Universities, Urbanización Montepríncipe, Monteprincipe Avenue, 28668, Madrid, Spain
| | - Arantzazu Barquín
- Laboratory of Innovation in Oncology, HM CIOCC MADRID (Centro Integral Oncológico Clara Campal), Hospital Universitario HM Sanchinarro, HM Hospitales, Madrid, Spain
- Department of Genitourinary and Gynecological Tumors, Hospital Universitario HM Sanchinarro, HM Hospitales, Madrid, Spain
- Institute of Applied Molecular Medicine (IMMA), Department of Basic Medical Sciences, Facultad de Medicina, Universidad San Pablo CEU, CEU Universities, Urbanización Montepríncipe, Monteprincipe Avenue, 28668, Madrid, Spain
| | - Jesús García-Donas
- Laboratory of Innovation in Oncology, HM CIOCC MADRID (Centro Integral Oncológico Clara Campal), Hospital Universitario HM Sanchinarro, HM Hospitales, Madrid, Spain.
- Department of Genitourinary and Gynecological Tumors, Hospital Universitario HM Sanchinarro, HM Hospitales, Madrid, Spain.
- Institute of Applied Molecular Medicine (IMMA), Department of Basic Medical Sciences, Facultad de Medicina, Universidad San Pablo CEU, CEU Universities, Urbanización Montepríncipe, Monteprincipe Avenue, 28668, Madrid, Spain.
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23
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Yu Y, Yu M, Li Y, Zhou X, Tian T, Du Y, Tu Z, Huang M. Rapid response to monotherapy with MEK inhibitor trametinib for a lung adenocarcinoma patient harboring primary SDN1-BRAF fusion: A case report and literature review. Front Oncol 2022; 12:945620. [PMID: 36059688 PMCID: PMC9437588 DOI: 10.3389/fonc.2022.945620] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 07/26/2022] [Indexed: 11/19/2022] Open
Abstract
BRAF gene has been identified as an oncogenic driver and a potential target in various malignancies. BRAF fusions are one subtype of BRAF alterations with a rare frequency. Here, we first report a previously treated advanced lung adenocarcinoma patient with de novo SND1-BRAF fusion who achieves partial response to the MAK inhibitor trametinib. We also provide a literature review on targeted therapies for BRAF fusions.
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Affiliation(s)
- Yang Yu
- Department of Thoracic Oncology and State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Min Yu
- Department of Thoracic Oncology and State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Yanying Li
- Department of Thoracic Oncology and State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Xiaojuan Zhou
- Department of Thoracic Oncology and State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Tian Tian
- West China school of medicine, Sichuan University, Chengdu, China
| | - Yijia Du
- West China school of medicine, Sichuan University, Chengdu, China
| | - Zegui Tu
- West China school of medicine, Sichuan University, Chengdu, China
| | - Meijuan Huang
- Department of Thoracic Oncology and State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
- *Correspondence: Meijuan Huang,
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24
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Philip PA, Azar I, Xiu J, Hall MJ, Hendifar AE, Lou E, Hwang JJ, Gong J, Feldman R, Ellis M, Stafford P, Spetzler D, Khushman MM, Sohal D, Lockhart AC, Weinberg BA, El-Deiry WS, Marshall J, Shields AF, Korn WM. Molecular Characterization of KRAS Wild-type Tumors in Patients with Pancreatic Adenocarcinoma. Clin Cancer Res 2022; 28:2704-2714. [PMID: 35302596 PMCID: PMC9541577 DOI: 10.1158/1078-0432.ccr-21-3581] [Citation(s) in RCA: 104] [Impact Index Per Article: 34.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 12/20/2021] [Accepted: 03/16/2022] [Indexed: 11/16/2022]
Abstract
PURPOSE KRAS mutation (MT) is a major oncogenic driver in pancreatic ductal adenocarcinoma (PDAC). A small subset of PDACs harbor KRAS wild-type (WT). We aim to characterize the molecular profiles of KRAS WT PDAC to uncover new pathogenic drivers and offer targeted treatments. EXPERIMENTAL DESIGN Tumor tissue obtained from surgical or biopsy material was subjected to next-generation DNA/RNA sequencing, microsatellite instability (MSI) and mismatch repair status determination. RESULTS Of the 2,483 patients (male 53.7%, median age 66 years) studied, 266 tumors (10.7%) were KRAS WT. The most frequently mutated gene in KRAS WT PDAC was TP53 (44.5%), followed by BRAF (13.0%). Multiple mutations within the DNA-damage repair (BRCA2, ATM, BAP1, RAD50, FANCE, PALB2), chromatin remodeling (ARID1A, PBRM1, ARID2, KMT2D, KMT2C, SMARCA4, SETD2), and cell-cycle control pathways (CDKN2A, CCND1, CCNE1) were detected frequently. There was no statistically significant difference in PD-L1 expression between KRAS WT (15.8%) and MT (17%) tumors. However, KRAS WT PDAC were more likely to be MSI-high (4.7% vs. 0.7%; P < 0.05), tumor mutational burden-high (4.5% vs. 1%; P < 0.05), and exhibit increased infiltration of CD8+ T cells, natural killer cells, and myeloid dendritic cells. KRAS WT PDACs exhibited gene fusions of BRAF (6.6%), FGFR2 (5.2%), ALK (2.6%), RET (1.3%), and NRG1 (1.3%), as well as amplification of FGF3 (3%), ERBB2 (2.2%), FGFR3 (1.8%), NTRK (1.8%), and MET (1.3%). Real-world evidence reveals a survival advantage of KRAS WT patients in overall cohorts as well as in patients treated with gemcitabine/nab-paclitaxel or 5-FU/oxaliplatin. CONCLUSIONS KRAS WT PDAC represents 10.7% of PDAC and is enriched with targetable alterations, including immuno-oncologic markers. Identification of KRAS WT patients in clinical practice may expand therapeutic options in a clinically meaningful manner.
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Affiliation(s)
- Philip A Philip
- Wayne State University, School of Medicine, Karmanos Cancer Center, Detroit, Michigan
| | - Ibrahim Azar
- Wayne State University, School of Medicine, Karmanos Cancer Center, Detroit, Michigan
| | | | | | | | - Emil Lou
- Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota
| | | | - Jun Gong
- Samuel Oschin Cancer Center, Cedars-Sinai Medical Center, Los Angeles, California
| | | | | | | | | | - Moh'd M Khushman
- Medical Oncology, The University of South Alabama, Mitchell Cancer Institute, Mobile, Alabama
| | | | - A Craig Lockhart
- Medical University of South Carolina, Charleston, South Carolina
| | | | - Wafik S El-Deiry
- Cancer Center at Brown University, The Warren Alpert Medical School, Brown University, Providence, Rhode Island
| | - John Marshall
- Georgetown University, Washington, District of Columbia
| | - Anthony F Shields
- Wayne State University, School of Medicine, Karmanos Cancer Center, Detroit, Michigan
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25
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Darabi S, Elliott A, Braxton DR, Zeng J, Hodges K, Poorman K, Swensen J, Shanthappa BU, Hinton JP, Gibney GT, Moser J, Phung T, Atkins MB, In GK, Korn WM, Eisenberg BL, Demeure MJ. Transcriptional Profiling of Malignant Melanoma Reveals Novel and Potentially Targetable Gene Fusions. Cancers (Basel) 2022; 14:cancers14061505. [PMID: 35326655 PMCID: PMC8946593 DOI: 10.3390/cancers14061505] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2022] [Revised: 03/08/2022] [Accepted: 03/10/2022] [Indexed: 11/24/2022] Open
Abstract
Simple Summary Malignant melanoma is a complex disease that is estimated to claim over 7000 lives in the United States in 2021. Although recent advances in genomic technology have helped with the identification of driver variants, molecular studies and clinical trials have often focused on prevalent alterations, such as the BRAF-V600E mutation. With the inclusion of whole transcriptome sequencing, molecular profiling of melanomas has identified gene fusions and revealed gene expression profiles that are consistent with the activation of signaling pathways by common driver mutations. Patients harboring such fusions may benefit from currently approved targeted therapies and should be considered in the design of future clinical trials to further personalize treatments for patients with malignant melanoma. Abstract Invasive melanoma is the deadliest type of skin cancer, with 101,110 expected cases to be diagnosed in 2021. Recurrent BRAF and NRAS mutations are well documented in melanoma. Biologic implications of gene fusions and the efficacy of therapeutically targeting them remains unknown. Retrospective review of patient samples that underwent next-generation sequencing of the exons of 592 cancer-relevant genes and whole transcriptome sequencing for the detection of gene fusion events and gene expression profiling. Expression of PDL1 and ERK1/2 was assessed by immunohistochemistry (IHC). There were 33 (2.6%) cases with oncogenic fusions (14 novel), involving BRAF, RAF1, PRKCA, TERT, AXL, and FGFR3. MAPK pathway-associated genes were over-expressed in BRAF and RAF1 fusion-positive tumors in absence of other driver alterations. Increased expression in tumors with PRKCA and TERT fusions was concurrent with MAPK pathway alterations. For a subset of samples with available tissue, increased phosphorylation of ERK1/2 was observed in BRAF, RAF1, and PRKCA fusion-positive tumors. Oncogenic gene fusions are associated with transcriptional activation of the MAPK pathway, suggesting they could be therapeutic targets with available inhibitors. Additional analyses to fully characterize the oncogenic effects of these fusions may support biomarker driven clinical trials.
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Affiliation(s)
- Sourat Darabi
- Hoag Family Cancer Institute, Newport Beach, CA 92663, USA; (D.R.B.); (B.L.E.); (M.J.D.)
- Correspondence:
| | - Andrew Elliott
- Caris Life Sciences, Phoenix, AZ 85040, USA; (A.E.); (J.Z.); (K.H.); (K.P.); (J.S.); (B.U.S.); (J.P.H.); (W.M.K.)
| | - David R. Braxton
- Hoag Family Cancer Institute, Newport Beach, CA 92663, USA; (D.R.B.); (B.L.E.); (M.J.D.)
| | - Jia Zeng
- Caris Life Sciences, Phoenix, AZ 85040, USA; (A.E.); (J.Z.); (K.H.); (K.P.); (J.S.); (B.U.S.); (J.P.H.); (W.M.K.)
| | - Kurt Hodges
- Caris Life Sciences, Phoenix, AZ 85040, USA; (A.E.); (J.Z.); (K.H.); (K.P.); (J.S.); (B.U.S.); (J.P.H.); (W.M.K.)
| | - Kelsey Poorman
- Caris Life Sciences, Phoenix, AZ 85040, USA; (A.E.); (J.Z.); (K.H.); (K.P.); (J.S.); (B.U.S.); (J.P.H.); (W.M.K.)
| | - Jeff Swensen
- Caris Life Sciences, Phoenix, AZ 85040, USA; (A.E.); (J.Z.); (K.H.); (K.P.); (J.S.); (B.U.S.); (J.P.H.); (W.M.K.)
| | - Basavaraja U. Shanthappa
- Caris Life Sciences, Phoenix, AZ 85040, USA; (A.E.); (J.Z.); (K.H.); (K.P.); (J.S.); (B.U.S.); (J.P.H.); (W.M.K.)
| | - James P. Hinton
- Caris Life Sciences, Phoenix, AZ 85040, USA; (A.E.); (J.Z.); (K.H.); (K.P.); (J.S.); (B.U.S.); (J.P.H.); (W.M.K.)
| | - Geoffrey T. Gibney
- Lombardi Comprehensive Cancer Center, MedStar Georgetown University Hospital, Washington, DC 20007, USA; (G.T.G.); (M.B.A.)
| | - Justin Moser
- Honor Health Research Institute, Scottsdale, AZ 85258, USA;
| | - Thuy Phung
- Department of Pathology, University of South Alabama, Mobile, AL 36617, USA;
| | - Michael B. Atkins
- Lombardi Comprehensive Cancer Center, MedStar Georgetown University Hospital, Washington, DC 20007, USA; (G.T.G.); (M.B.A.)
| | - Gino K. In
- Division of Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA;
| | - Wolfgang M. Korn
- Caris Life Sciences, Phoenix, AZ 85040, USA; (A.E.); (J.Z.); (K.H.); (K.P.); (J.S.); (B.U.S.); (J.P.H.); (W.M.K.)
| | - Burton L. Eisenberg
- Hoag Family Cancer Institute, Newport Beach, CA 92663, USA; (D.R.B.); (B.L.E.); (M.J.D.)
- Division of Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA;
| | - Michael J. Demeure
- Hoag Family Cancer Institute, Newport Beach, CA 92663, USA; (D.R.B.); (B.L.E.); (M.J.D.)
- Translational Genomics Research Institution, Phoenix, AZ 85004, USA
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Awada G, Neyns B. Melanoma with genetic alterations beyond the BRAFV600 mutation: management and new insights. Curr Opin Oncol 2022; 34:115-122. [PMID: 35050937 DOI: 10.1097/cco.0000000000000817] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
PURPOSE OF REVIEW Molecular-targeted therapy with BRAF-/MEK-inhibitors has shown impressive activity in patients with advanced BRAFV600 mutant melanoma. In this review, we aim to summarize recent data and possible future therapeutic strategies involving small-molecule molecular-targeted therapies for advanced BRAFV600 wild-type melanoma. RECENT FINDINGS In patients with NRASQ61 mutant melanoma, downstream MEK-inhibition has shown some albeit low activity. MEK-inhibitors combined with novel RAF dimer inhibitors, such as belvarafenib, or with CDK4/6-inhibitors have promising activity in NRAS mutant melanoma in early-phase trials. In patients with non-V600 BRAF mutant melanoma, MEK-inhibition with or without BRAF-inhibition appears to be effective, although large-scale prospective trials are lacking. As non-V600 BRAF mutants signal as dimers, novel RAF dimer inhibitors are also under investigation in this setting. MEK-inhibition is under investigation in NF1 mutant melanoma. Finally, in patients with BRAF/NRAS/NF1 wild-type melanoma, imatinib or nilotinib can be effective in cKIT mutant melanoma. Despite preclinical data suggesting synergistic activity, the combination of the MEK-inhibitor cobimetinib with the immune checkpoint inhibitor atezolizumab was not superior to the immune checkpoint inhibitor pembrolizumab. SUMMARY As of today, no molecular-targeted therapies have shown to improve survival in patients with advanced BRAFV600 wild-type melanoma. Combinatorial strategies, involving MEK-inhibitors, RAF dimer inhibitors and CDK4/6-inhibitors, are currently under investigation and have promising activity in advanced BRAFV600 wild-type melanoma.
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Affiliation(s)
- Gil Awada
- Department of Medical Oncology, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Belgium
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Li J, Lu H, Ng PKS, Pantazi A, Ip CKM, Jeong KJ, Amador B, Tran R, Tsang YH, Yang L, Song X, Dogruluk T, Ren X, Hadjipanayis A, Bristow CA, Lee S, Kucherlapati M, Parfenov M, Tang J, Seth S, Mahadeshwar HS, Mojumdar K, Zeng D, Zhang J, Protopopov A, Seidman JG, Creighton CJ, Lu Y, Sahni N, Shaw KR, Meric-Bernstam F, Futreal A, Chin L, Scott KL, Kucherlapati R, Mills GB, Liang H. A functional genomic approach to actionable gene fusions for precision oncology. SCIENCE ADVANCES 2022; 8:eabm2382. [PMID: 35138907 PMCID: PMC8827659 DOI: 10.1126/sciadv.abm2382] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Accepted: 12/16/2021] [Indexed: 06/01/2023]
Abstract
Fusion genes represent a class of attractive therapeutic targets. Thousands of fusion genes have been identified in patients with cancer, but the functional consequences and therapeutic implications of most of these remain largely unknown. Here, we develop a functional genomic approach that consists of efficient fusion reconstruction and sensitive cell viability and drug response assays. Applying this approach, we characterize ~100 fusion genes detected in patient samples of The Cancer Genome Atlas, revealing a notable fraction of low-frequency fusions with activating effects on tumor growth. Focusing on those in the RTK-RAS pathway, we identify a number of activating fusions that can markedly affect sensitivity to relevant drugs. Last, we propose an integrated, level-of-evidence classification system to prioritize gene fusions systematically. Our study reiterates the urgent clinical need to incorporate similar functional genomic approaches to characterize gene fusions, thereby maximizing the utility of gene fusions for precision oncology.
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Affiliation(s)
- Jun Li
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Hengyu Lu
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
| | - Patrick Kwok-Shing Ng
- Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Angeliki Pantazi
- Department of Genetics, Harvard Medical School, Division of Genetics, Brigham and Women’s Hospital, Boston, MA, USA
| | - Carman Ka Man Ip
- Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Kang Jin Jeong
- Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Bianca Amador
- Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Richard Tran
- Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yiu Huen Tsang
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
| | - Lixing Yang
- Ben May Department for Cancer Research and Department of Human Genetics, The University of Chicago, Chicago, IL, USA
| | - Xingzhi Song
- Department of Genomic Medicine, The University of MD Anderson Cancer Center, Houston, TX, USA
- Institute for Applied Cancer Science, The University of MD Anderson Cancer Center, Houston, TX, USA
| | - Turgut Dogruluk
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
| | - Xiaojia Ren
- Department of Genetics, Harvard Medical School, Division of Genetics, Brigham and Women’s Hospital, Boston, MA, USA
| | - Angela Hadjipanayis
- Department of Genetics, Harvard Medical School, Division of Genetics, Brigham and Women’s Hospital, Boston, MA, USA
| | - Christopher A. Bristow
- Department of Genomic Medicine, The University of MD Anderson Cancer Center, Houston, TX, USA
- Institute for Applied Cancer Science, The University of MD Anderson Cancer Center, Houston, TX, USA
| | - Semin Lee
- Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA
| | - Melanie Kucherlapati
- Department of Genetics, Harvard Medical School, Division of Genetics, Brigham and Women’s Hospital, Boston, MA, USA
| | - Michael Parfenov
- Department of Genetics, Harvard Medical School, Division of Genetics, Brigham and Women’s Hospital, Boston, MA, USA
| | - Jiabin Tang
- Department of Genomic Medicine, The University of MD Anderson Cancer Center, Houston, TX, USA
- Institute for Applied Cancer Science, The University of MD Anderson Cancer Center, Houston, TX, USA
| | - Sahil Seth
- Department of Genomic Medicine, The University of MD Anderson Cancer Center, Houston, TX, USA
- Institute for Applied Cancer Science, The University of MD Anderson Cancer Center, Houston, TX, USA
| | - Harshad S. Mahadeshwar
- Department of Genomic Medicine, The University of MD Anderson Cancer Center, Houston, TX, USA
- Institute for Applied Cancer Science, The University of MD Anderson Cancer Center, Houston, TX, USA
| | - Kamalika Mojumdar
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Dong Zeng
- Department of Genomic Medicine, The University of MD Anderson Cancer Center, Houston, TX, USA
- Institute for Applied Cancer Science, The University of MD Anderson Cancer Center, Houston, TX, USA
| | - Jianhua Zhang
- Department of Genomic Medicine, The University of MD Anderson Cancer Center, Houston, TX, USA
- Institute for Applied Cancer Science, The University of MD Anderson Cancer Center, Houston, TX, USA
| | - Alexei Protopopov
- Department of Genomic Medicine, The University of MD Anderson Cancer Center, Houston, TX, USA
- Institute for Applied Cancer Science, The University of MD Anderson Cancer Center, Houston, TX, USA
| | - Jonathan G. Seidman
- Department of Genetics, Harvard Medical School, Division of Genetics, Brigham and Women’s Hospital, Boston, MA, USA
| | - Chad J. Creighton
- Department of Medicine, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA
| | - Yiling Lu
- Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Genomic Medicine, The University of MD Anderson Cancer Center, Houston, TX, USA
| | - Nidhi Sahni
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX, USA
- Graduate Program in Quantitative and Computational Biosciences, Baylor College of Medicine, Houston, TX, USA
| | - Kenna R. Shaw
- Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Funda Meric-Bernstam
- Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Andrew Futreal
- Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Genomic Medicine, The University of MD Anderson Cancer Center, Houston, TX, USA
| | - Lynda Chin
- Department of Genomic Medicine, The University of MD Anderson Cancer Center, Houston, TX, USA
- Institute for Applied Cancer Science, The University of MD Anderson Cancer Center, Houston, TX, USA
- Dell Medical School, The University of Texas Austin, Austin, TX, USA
| | - Kenneth L. Scott
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
- Department of Medicine, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA
| | - Raju Kucherlapati
- Department of Genetics, Harvard Medical School, Division of Genetics, Brigham and Women’s Hospital, Boston, MA, USA
| | - Gordon B. Mills
- Division of Oncologic Sciences, Knight Cancer Institute, Oregon Health Sciences University, Portland, OR, USA
| | - Han Liang
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Graduate Program in Quantitative and Computational Biosciences, Baylor College of Medicine, Houston, TX, USA
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Liprins in oncogenic signaling and cancer cell adhesion. Oncogene 2021; 40:6406-6416. [PMID: 34654889 PMCID: PMC8602034 DOI: 10.1038/s41388-021-02048-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Revised: 09/21/2021] [Accepted: 09/28/2021] [Indexed: 12/30/2022]
Abstract
Liprins are a multifunctional family of scaffold proteins, identified by their involvement in several important neuronal functions related to signaling and organization of synaptic structures. More recently, the knowledge on the liprin family has expanded from neuronal functions to processes relevant to cancer progression, including cell adhesion, cell motility, cancer cell invasion, and signaling. These proteins consist of regions, which by prediction are intrinsically disordered, and may be involved in the assembly of supramolecular structures relevant for their functions. This review summarizes the current understanding of the functions of liprins in different cellular processes, with special emphasis on liprins in tumor progression. The available data indicate that liprins may be potential biomarkers for cancer progression and may have therapeutic importance.
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Torrence D, Xie Z, Zhang L, Chi P, Antonescu CR. Gastrointestinal stromal tumors with BRAF gene fusions. A report of two cases showing low or absent KIT expression resulting in diagnostic pitfalls. Genes Chromosomes Cancer 2021; 60:789-795. [PMID: 34398495 DOI: 10.1002/gcc.22991] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 08/12/2021] [Accepted: 08/13/2021] [Indexed: 01/02/2023] Open
Abstract
Although most gastrointestinal stromal tumors (GISTs) exhibit activating mutations in either KIT or PDGFRA, rare cases have shown to be driven by gene fusions involving kinases, mainly involving NTRK3, and rarely BRAF or FGFR1. BRAF gene rearrangements have been described in only two patients to date, as separate case reports. In addition, BRAF V600E mutation is an uncommon but established oncogenic pathway in GIST. In this report, we describe two new GIST cases harboring novel BRAF fusion genes, arising in two young-adult women (37 and 40 years of age) in the small bowel and distal esophagus, both with a spindle cell phenotype. The small bowel GIST measured 2.8 cm and showed a high cellularity and a mitotic rate of 20/50 HPFs, while the esophageal lesion measured 7 cm and 1/50 HPFs. Immunohistochemically, both tumors showed diffuse reactivity for DOG1, while KIT/CD117 was weakly positive in the small bowel GIST and completely negative in the esophageal tumor. Based on these findings, the latter case was misinterpreted as a low-grade myxoid leiomyosarcoma, as it showed a myxoid stroma, reactivity for SMA and focal positivity for desmin. Archer FusionPlex revealed a fusion between BRAF with either AGAP3 or MKRN1 gene partners. Moreover, MSK-IMPACT DNA targeted sequencing confirmed both fusions but did not identify additional mutations. In one case with available material, the BRAF gene rearrangement was also validated by FISH. The recognition of BRAF fusion-positive GISTs is critical as it may be associated with a low level of KIT expression and may result in diagnostic challenges with significant impact on therapeutic management. The clinical benefit with KIT inhibitors, such as imatinib, remains to be determined.
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Affiliation(s)
- Dianne Torrence
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Ziyu Xie
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Lei Zhang
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Ping Chi
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.,Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.,Department of Medicine, Weill Cornell Medical College, New York, New York, USA
| | - Cristina R Antonescu
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA
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Revythis A, Shah S, Kutka M, Moschetta M, Ozturk MA, Pappas-Gogos G, Ioannidou E, Sheriff M, Rassy E, Boussios S. Unraveling the Wide Spectrum of Melanoma Biomarkers. Diagnostics (Basel) 2021; 11:diagnostics11081341. [PMID: 34441278 PMCID: PMC8391989 DOI: 10.3390/diagnostics11081341] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Revised: 07/21/2021] [Accepted: 07/22/2021] [Indexed: 12/24/2022] Open
Abstract
The use of biomarkers in medicine has become essential in clinical practice in order to help with diagnosis, prognostication and prediction of treatment response. Since Alexander Breslow’s original report on “melanoma and prognostic values of thickness”, providing the first biomarker for melanoma, many promising new biomarkers have followed. These include serum markers, such as lactate dehydrogenase and S100 calcium-binding protein B. However, as our understanding of the DNA mutational profile progresses, new gene targets and proteins have been identified. These include point mutations, such as mutations of the BRAF gene and tumour suppressor gene tP53. At present, only a small number of the available biomarkers are being utilised, but this may soon change as more studies are published. The aim of this article is to provide a comprehensive review of melanoma biomarkers and their utility for current and, potentially, future clinical practice.
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Affiliation(s)
- Antonios Revythis
- Department of Medical Oncology, Medway NHS Foundation Trust, Windmill Road, Gillingham ME7 5NY, UK; (A.R.); (S.S.); (M.K.)
| | - Sidrah Shah
- Department of Medical Oncology, Medway NHS Foundation Trust, Windmill Road, Gillingham ME7 5NY, UK; (A.R.); (S.S.); (M.K.)
| | - Mikolaj Kutka
- Department of Medical Oncology, Medway NHS Foundation Trust, Windmill Road, Gillingham ME7 5NY, UK; (A.R.); (S.S.); (M.K.)
| | - Michele Moschetta
- CHUV, Lausanne University Hospital, Rue du Bugnon, 21 CH-1011 Lausanne, Switzerland;
| | - Mehmet Akif Ozturk
- Department of Internal Medicine, School of Medicine, Bahcesehir University, Istanbul 34353, Turkey;
| | - George Pappas-Gogos
- Department of Surgery, University Hospital of Ioannina, 45111 Ioannina, Greece;
| | - Evangelia Ioannidou
- Department of Paediatrics and Child Health, West Suffolk Hospital NHS Foundation Trust, Hardwick Lane, Bury St Edmunds IP33 2QZ, UK;
| | - Matin Sheriff
- Department of Urology, Medway NHS Foundation Trust, Windmill Road, Gillingham ME7 5NY, UK;
| | - Elie Rassy
- Department of Cancer Medicine, Gustave Roussy Institut, 94805 Villejuif, France;
| | - Stergios Boussios
- Department of Medical Oncology, Medway NHS Foundation Trust, Windmill Road, Gillingham ME7 5NY, UK; (A.R.); (S.S.); (M.K.)
- Faculty of Life Sciences & Medicine, School of Cancer & Pharmaceutical Sciences, King’s College London, London SE1 9RT, UK
- AELIA Organization, 9th Km Thessaloniki-Thermi, 57001 Thessaloniki, Greece
- Correspondence: or or
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Chew SM, Lucas M, Brady M, Kelly CM. SKAP2-BRAF fusion and response to an MEK inhibitor in a patient with metastatic melanoma resistant to immunotherapy. BMJ Case Rep 2021; 14:14/6/e238494. [PMID: 34167970 PMCID: PMC8230919 DOI: 10.1136/bcr-2020-238494] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Abstract
A woman in her 40s presented to the emergency department with headache and unintentional weight loss in September 2018. Investigations revealed a widely metastatic pan-negative melanoma of unknown primary. She had multiple lines of treatment including combination immunotherapy and chemotherapy. Next-generation sequencing identified an SKAP2-BRAF fusion protein, and she was commenced on an MEK inhibitor in September 2019 with a partial response seen on restaging scans after 6 weeks and a dramatic fall in her lactate dehydrogenase from 2248 IU/L to 576 IU/L. Unfortunately, the response was not maintained and she died from progression of her cancer in January 2020. SKAP2-BRAF fusions have a dimerisation domain that paradoxically activates the mitogen-activated protein kinase pathway, resulting in hyperproliferation if first-generation or second-generation BRAF inhibitors are used. Our knowledge is limited regarding the complex effects of targeted therapy in rare BRAF fusion proteins.
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Affiliation(s)
- Sonya Minmin Chew
- Medical Oncology, Mater Misericordiae University Hospital, Dublin, Ireland
| | - Mairi Lucas
- Medical Oncology, Mater Misericordiae University Hospital, Dublin, Ireland
| | - Michelle Brady
- Medical Oncology, Mater Misericordiae University Hospital, Dublin, Ireland
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Botton T, Talevich E, Mishra VK, Zhang T, Shain AH, Berquet C, Gagnon A, Judson RL, Ballotti R, Ribas A, Herlyn M, Rocchi S, Brown KM, Hayward NK, Yeh I, Bastian BC. Genetic Heterogeneity of BRAF Fusion Kinases in Melanoma Affects Drug Responses. Cell Rep 2020; 29:573-588.e7. [PMID: 31618628 DOI: 10.1016/j.celrep.2019.09.009] [Citation(s) in RCA: 70] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2017] [Revised: 07/26/2019] [Accepted: 09/04/2019] [Indexed: 12/15/2022] Open
Abstract
BRAF fusions are detected in numerous neoplasms, but their clinical management remains unresolved. We identified six melanoma lines harboring BRAF fusions representative of the clinical cases reported in the literature. Their unexpected heterogeneous responses to RAF and MEK inhibitors could be categorized upon specific features of the fusion kinases. Higher expression level correlated with resistance, and fusion partners containing a dimerization domain promoted paradoxical activation of the mitogen-activated protein kinase (MAPK) pathway and hyperproliferation in response to first- and second-generation RAF inhibitors. By contrast, next-generation αC-IN/DFG-OUT RAF inhibitors blunted paradoxical activation across all lines and had their therapeutic efficacy further increased in vitro and in vivo by combination with MEK inhibitors, opening perspectives in the clinical management of tumors harboring BRAF fusions.
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Affiliation(s)
- Thomas Botton
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Dermatology, University of California, San Francisco, San Francisco, CA 94115, USA; Department of Pathology, University of California, San Francisco, San Francisco, CA 94115, USA.
| | - Eric Talevich
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Dermatology, University of California, San Francisco, San Francisco, CA 94115, USA; Department of Pathology, University of California, San Francisco, San Francisco, CA 94115, USA
| | - Vivek Kumar Mishra
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Dermatology, University of California, San Francisco, San Francisco, CA 94115, USA; Department of Pathology, University of California, San Francisco, San Francisco, CA 94115, USA
| | - Tongwu Zhang
- Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MA 20892, USA
| | - A Hunter Shain
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Dermatology, University of California, San Francisco, San Francisco, CA 94115, USA; Department of Pathology, University of California, San Francisco, San Francisco, CA 94115, USA
| | - Céline Berquet
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Dermatology, University of California, San Francisco, San Francisco, CA 94115, USA; Department of Pathology, University of California, San Francisco, San Francisco, CA 94115, USA
| | - Alexander Gagnon
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Dermatology, University of California, San Francisco, San Francisco, CA 94115, USA; Department of Pathology, University of California, San Francisco, San Francisco, CA 94115, USA
| | - Robert L Judson
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Dermatology, University of California, San Francisco, San Francisco, CA 94115, USA
| | - Robert Ballotti
- U1065, Institut National de la Santé et de la Recherche Médicale, Centre Méditerranéen de Médecine Moléculaire, Université Côte d'Azur, 06200 Nice, France
| | - Antoni Ribas
- Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Meenhard Herlyn
- Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The Wistar Institute, Philadelphia, PA 19104, USA
| | - Stéphane Rocchi
- U1065, Institut National de la Santé et de la Recherche Médicale, Centre Méditerranéen de Médecine Moléculaire, Université Côte d'Azur, 06200 Nice, France
| | - Kevin M Brown
- Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MA 20892, USA
| | - Nicholas K Hayward
- Oncogenomics Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia
| | - Iwei Yeh
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Dermatology, University of California, San Francisco, San Francisco, CA 94115, USA; Department of Pathology, University of California, San Francisco, San Francisco, CA 94115, USA
| | - Boris C Bastian
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Dermatology, University of California, San Francisco, San Francisco, CA 94115, USA; Department of Pathology, University of California, San Francisco, San Francisco, CA 94115, USA.
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33
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The limitations of targeting MEK signalling in Glioblastoma therapy. Sci Rep 2020; 10:7401. [PMID: 32366879 PMCID: PMC7198577 DOI: 10.1038/s41598-020-64289-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Accepted: 04/15/2020] [Indexed: 01/16/2023] Open
Abstract
Glioblastoma (GB) is a highly aggressive, difficult to treat brain tumour. Successful treatment, consisting of maximal safe tumour de-bulking, followed by radiotherapy and treatment with the alkylating agent Temozolomide (TMZ), can extend patient survival to approximately 15 months. Combination treatments based on the inhibition of the PI3K pathway, which is the most frequently activated signalling cascade in GB, have so far only shown limited therapeutic success. Here, we use the clinically approved MEK inhibitor Trametinib to investigate its potential use in managing GB. Trametinib has a strong anti-proliferative effect on established GB cell lines, stem cell-like cells and their differentiated progeny and while it does not enhance anti-proliferative and cell death-inducing properties of the standard treatment, i.e. exposure to radiation or TMZ, neither does MEK inhibition block their effectiveness. However, upon MEK inhibition some cell populations appear to favour cell-substrate interactions in a sprouting assay and become more invasive in the Chorioallantoic Membrane assay, which assesses cell penetration into an organic membrane. While this increased invasion can be modulated by additional inhibition of the PI3K signalling cascade, there is no apparent benefit of blocking MEK compared to targeting PI3K.
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34
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Johnson DB, Zhao F, Noel M, Riely GJ, Mitchell EP, Wright JJ, Chen HX, Gray RJ, Li S, McShane LM, Rubinstein LV, Patton D, Williams PM, Hamilton SR, Conley BA, Arteaga CL, Harris LN, O'Dwyer PJ, Chen AP, Flaherty KT. Trametinib Activity in Patients with Solid Tumors and Lymphomas Harboring BRAF Non-V600 Mutations or Fusions: Results from NCI-MATCH (EAY131). Clin Cancer Res 2020; 26:1812-1819. [PMID: 31924734 PMCID: PMC7165046 DOI: 10.1158/1078-0432.ccr-19-3443] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Revised: 12/16/2019] [Accepted: 01/07/2020] [Indexed: 11/16/2022]
Abstract
PURPOSE Substantial preclinical evidence and case reports suggest that MEK inhibition is an active approach in tumors with BRAF mutations outside the V600 locus, and in BRAF fusions. Thus, Subprotocol R of the NCI-MATCH study tested the MEK inhibitor trametinib in this population. PATIENTS AND METHODS The NCI-MATCH study performed genomic profiling on tumor samples from patients with solid tumors and lymphomas progressing on standard therapies or with no standard treatments. Patients with prespecified fusions and non-V600 mutations in BRAF were assigned to Subprotocol R using the NCI-MATCHBOX algorithm. The primary endpoint was objective response rate (ORR). RESULTS Among 50 patients assigned, 32 were eligible and received therapy with trametinib. Of these, 1 had a BRAF fusion and 31 had BRAF mutations (13 and 19 with class 2 and 3 mutations, respectively). There were no complete responses; 1 patient (3%) had a confirmed partial response (patient with breast ductal adenocarcinoma with BRAF G469E mutation) and 10 patients had stable disease as best response (clinical benefit rate 34%). Median progression-free survival (PFS) was 1.8 months, and median overall survival was 5.7 months. Exploratory subgroup analyses showed that patients with colorectal adenocarcinoma (n = 8) had particularly poor PFS. No new toxicity signals were identified. CONCLUSIONS Trametinib did not show promising clinical activity in patients with tumors harboring non-V600 BRAF mutations, and the subprotocol did not meet its primary endpoint.
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Affiliation(s)
| | - Fengmin Zhao
- Dana-Farber Cancer Institute-ECOG-ACRIN Biostatistics Center, Boston, Massachusetts
| | - Marcus Noel
- University of Rochester, Rochester, New York
| | | | - Edith P Mitchell
- Thomas Jefferson University Hospital, Philadelphia, Pennsylvania
| | | | | | - Robert J Gray
- Dana-Farber Cancer Institute-ECOG-ACRIN Biostatistics Center, Boston, Massachusetts
| | - Shuli Li
- Dana-Farber Cancer Institute-ECOG-ACRIN Biostatistics Center, Boston, Massachusetts
| | | | | | | | - P Mickey Williams
- Frederick National Laboratory for Cancer Research, Bethesda, Maryland
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35
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Polypoid Atypical Spitz Tumor With a Fibrosclerotic Stroma, CLIP2-BRAF Fusion, and Homozygous Loss of 9p21. Am J Dermatopathol 2020; 42:204-207. [DOI: 10.1097/dad.0000000000001502] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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36
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Lee SJ, Hong JY, Kim K, Kim KM, Kang SY, Lee T, Kim ST, Park SH, Park YS, Lim HY, Kang WK, Lee J, Park JO. Detection of Fusion Genes Using a Targeted RNA Sequencing Panel in Gastrointestinal and Rare Cancers. JOURNAL OF ONCOLOGY 2020; 2020:4659062. [PMID: 32411236 PMCID: PMC7204148 DOI: 10.1155/2020/4659062] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Revised: 12/09/2019] [Accepted: 12/19/2019] [Indexed: 12/22/2022]
Abstract
Successful identification and targeting of oncogenic gene fusion is a major breakthrough in cancer treatment. Here, we investigate the therapeutic implications and feasibility of using a targeted RNA sequencing panel to identify fusion genes in gastrointestinal and rare cancers. From February through December 2017, patients with gastrointestinal, hepatobiliary, gynecologic, sarcoma, or rare cancers were recruited for a clinical sequencing project at Samsung Medical Center (NCT #02593578). The median age of the patients was 58 years (range, 31-81 years), and the male-to-female ratio was 1.3 : 1. A total of 118 patients passed the quality control process for a next-generation sequencing- (NGS-) based targeted sequencing assay. The NGS-based targeted sequencing assay was performed to detect gene fusions in 36-53 cancer-implicated genes. The following cancer types were included in this study: 28 colorectal cancers, 27 biliary tract cancers, 25 gastric cancers, 18 soft tissue sarcomas, 9 pancreatic cancers, 6 ovarian cancers, and 9 other rare cancers. Strong fusion was detected in 25 samples (21.2%). We found that 5.9% (7/118) of patients had known targetable fusion genes involving NTRK1 (n=3), FGFR (n=3), and RET (n=1), and 10.2% (12/118) of patients had potentially targetable fusion genes involving RAF1 (n=4), BRAF (n=2), ALK (n=2), ROS1 (n=1), EGFR (n=1), and CLDN18 (n=2). Thus, we successfully identified a substantial proportion of patients harboring fusion genes by RNA panel sequencing of gastrointestinal/rare cancers. Targetable and potentially targetable involved fusion genes were NTRK1, RET, FGFR3, FGFR2, BRAF, RAF1, ALK, ROS1, and CLDN18. Detection of fusion genes by RNA panel sequencing may be beneficial in refractory patients with gastrointestinal/rare cancers.
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Affiliation(s)
- Su Jin Lee
- Division of Hematology-Oncology, Department of Medicine, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
- Division of Hematology-Oncology, Department of Internal Medicine, Ewha Womans University College of Medicine, Seoul, Republic of Korea
| | - Jung Yong Hong
- Division of Hematology-Oncology, Department of Medicine, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Kyung Kim
- Division of Hematology-Oncology, Department of Medicine, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Kyoung-Mee Kim
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - So Young Kang
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Taeyang Lee
- Division of Hematology-Oncology, Department of Medicine, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Seung Tae Kim
- Division of Hematology-Oncology, Department of Medicine, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Se Hoon Park
- Division of Hematology-Oncology, Department of Medicine, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Young Suk Park
- Division of Hematology-Oncology, Department of Medicine, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Ho Yeong Lim
- Division of Hematology-Oncology, Department of Medicine, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Won Ki Kang
- Division of Hematology-Oncology, Department of Medicine, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Jeeyun Lee
- Division of Hematology-Oncology, Department of Medicine, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Joon Oh Park
- Division of Hematology-Oncology, Department of Medicine, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
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37
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Le Flahec G, Briolais M, Guibourg B, Lemasson G, Grippari JL, Ledé F, Marcorelles P, Uguen A. Testing for BRAF fusions in patients with advanced BRAF/ NRAS/ KIT wild-type melanomas permits to identify patients who could benefit of anti-MEK targeted therapy. J Clin Pathol 2019; 73:116-119. [PMID: 31506288 DOI: 10.1136/jclinpath-2019-206026] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2019] [Revised: 08/26/2019] [Accepted: 09/02/2019] [Indexed: 12/15/2022]
Abstract
Beyond targeted therapy for patients with BRAF-mutated melanomas and immunotherapy in patients lacking BRAF mutations, anti-MEK therapy has been proposed in patients with advanced melanomas harbouring BRAF fusions. BRAF fusions diagnosis in patients with advanced melanomas is the subject of the present study. Using BRAF fluorescent in situ hybridisation (FISH), we searched for BRAF fusions in 74 samples of 66 patients with advanced BRAF/NRAS/KIT wild-type melanomas. We identified 2/66 (3%) patients with BRAF fusions in a brain metastasis of one patient and in a lymph node metastasis and in a cutaneous metastasis for the second patient with 90%-95% of tumour nuclei containing isolated 3'-BRAF FISH signals. As a result, we conclude that BRAF FISH in patients with advanced BRAF/NRAS/KIT wild-type melanomas is a valuable and easy-to-perform test to diagnose BRAF fusions and to identify patients who could benefit of anti-MEK targeted therapy.
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Affiliation(s)
| | | | | | | | | | | | | | - Arnaud Uguen
- Department of Pathology, CHRU Brest, Brest, France
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38
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Quan VL, Panah E, Zhang B, Shi K, Mohan LS, Gerami P. The role of gene fusions in melanocytic neoplasms. J Cutan Pathol 2019; 46:878-887. [DOI: 10.1111/cup.13521] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Revised: 05/28/2019] [Accepted: 05/29/2019] [Indexed: 02/06/2023]
Affiliation(s)
- Victor L. Quan
- Department of DermatologyFeinberg School of Medicine, Northwestern University Chicago Illinois
| | - Elnaz Panah
- Department of DermatologyFeinberg School of Medicine, Northwestern University Chicago Illinois
| | - Bin Zhang
- Department of DermatologyFeinberg School of Medicine, Northwestern University Chicago Illinois
| | - Katherine Shi
- Department of DermatologyFeinberg School of Medicine, Northwestern University Chicago Illinois
| | - Lauren S. Mohan
- Department of DermatologyFeinberg School of Medicine, Northwestern University Chicago Illinois
| | - Pedram Gerami
- Department of DermatologyFeinberg School of Medicine, Northwestern University Chicago Illinois
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Mitsudomi T. BRAF Fusion - Another Mechanism of Acquired Resistance to EGFR Tyrosine Kinase Inhibitors. J Thorac Oncol 2019; 14:764-765. [PMID: 31027740 DOI: 10.1016/j.jtho.2019.03.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2019] [Accepted: 03/04/2019] [Indexed: 10/27/2022]
Affiliation(s)
- Tetsuya Mitsudomi
- Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan.
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40
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Abstract
Cancers that appear morphologically similar often have dramatically different clinical features, respond variably to therapy and have a range of outcomes. Compelling evidence now demonstrates that differences in the molecular pathology of otherwise indistinguishable cancers substantially impact the clinical characteristics of the disease. Molecular subtypes now guide preclinical and clinical therapeutic development and treatment in many cancer types. The ability to predict optimal therapeutic strategies ahead of treatment improves overall patient outcomes, minimizing treatment-related morbidity and cost. Although clinical decision making based on histopathological criteria underpinned by robust data is well established in many cancer types, subtypes of pancreatic cancer do not currently inform treatment decisions. However, accumulating molecular data are defining subgroups in pancreatic cancer with distinct biology and potential subtype-specific therapeutic vulnerabilities, providing the opportunity to define a de novo clinically applicable molecular taxonomy. This Review summarizes current knowledge concerning the molecular subtyping of pancreatic cancer and explores future strategies for using a molecular taxonomy to guide therapeutic development and ultimately routine therapy with the overall goal of improving outcomes for this disease.
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Affiliation(s)
| | - Peter Bailey
- Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, Scotland, UK
| | - David K Chang
- Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, Scotland, UK
- West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK
| | - Andrew V Biankin
- Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, Scotland, UK.
- West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK.
- South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Liverpool, Australia.
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41
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Zhu YC, Wang WX, Xu CW, Zhuang W, Du KQ, Chen G, Lv TF, Song Y. A Patient With Lung Adenocarcinoma With BRAF Gene Fusion and Response to Vemurafenib. Clin Lung Cancer 2019; 20:e224-e228. [PMID: 30914311 DOI: 10.1016/j.cllc.2019.02.020] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Revised: 02/11/2019] [Accepted: 02/21/2019] [Indexed: 12/19/2022]
Affiliation(s)
- You-Cai Zhu
- Department of Thoracic Disease Diagnosis and Treatment Center, Zhejiang Rongjun Hospital, Jiaxing, Zhejiang, People's Republic of China
| | - Wen-Xian Wang
- Department of Chemotherapy, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, People's Republic of China.
| | - Chun-Wei Xu
- Department of Pathology, Fujian Cancer Hospital, Fujian Medical University Cancer Hospital, Fuzhou, Fujian, People's Republic of China.
| | - Wu Zhuang
- Department of Medical Thoracic Oncology, Fujian Cancer Hospital, Fujian Medical University Cancer Hospital, Fuzhou, Fujian, People's Republic of China
| | - Kai-Qi Du
- Department of Thoracic Disease Diagnosis and Treatment Center, Zhejiang Rongjun Hospital, Jiaxing, Zhejiang, People's Republic of China
| | - Gang Chen
- Department of Pathology, Fujian Cancer Hospital, Fujian Medical University Cancer Hospital, Fuzhou, Fujian, People's Republic of China
| | - Tang-Feng Lv
- Department of Respiratory Medicine, Jinling Hospital, Nanjing, Jiangsu, People's Republic of China
| | - Yong Song
- Department of Respiratory Medicine, Jinling Hospital, Nanjing, Jiangsu, People's Republic of China
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42
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Yaeger R, Corcoran RB. Targeting Alterations in the RAF-MEK Pathway. Cancer Discov 2019; 9:329-341. [PMID: 30770389 PMCID: PMC6397699 DOI: 10.1158/2159-8290.cd-18-1321] [Citation(s) in RCA: 307] [Impact Index Per Article: 51.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2018] [Revised: 12/26/2018] [Accepted: 01/16/2019] [Indexed: 12/13/2022]
Abstract
The MAPK pathway is one of the most commonly mutated oncogenic pathways in cancer. Although RAS mutations are the most frequent MAPK alterations, less frequent alterations in downstream components of the pathway, including the RAF and MEK genes, offer promising therapeutic opportunities. In addition to BRAFV600 mutations, for which several approved therapeutic regimens exist, other alterations in the RAF and MEK genes may provide more rare, but tractable, targets. However, recent studies have illustrated the complexity of MAPK signaling and highlighted that distinct alterations in these genes may have strikingly different properties. Understanding the unique functional characteristics of specific RAF and MEK alterations, reviewed herein, will be critical for developing effective therapeutic approaches for these targets. SIGNIFICANCE: Alterations in the RAF and MEK genes represent promising therapeutic targets in multiple cancer types. However, given the unique and complex signaling biology of the MAPK pathway, the diverse array of RAF and MEK alterations observed in cancer can possess distinct functional characteristics. As outlined in this review, understanding the key functional properties of different RAF and MEK alterations is fundamental to selecting the optimal therapeutic approach.
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Affiliation(s)
- Rona Yaeger
- Memorial Sloan Kettering Cancer Center, New York, New York.
| | - Ryan B Corcoran
- Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts.
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43
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Boussemart L, Nelson A, Wong M, Ross JS, Sosman J, Mehnert J, Daniels G, Kendra K, Ali SM, Miller VA, Schrock AB. Hybrid Capture-Based Genomic Profiling Identifies BRAF V600 and Non-V600 Alterations in Melanoma Samples Negative by Prior Testing. Oncologist 2019; 24:657-663. [PMID: 30683711 DOI: 10.1634/theoncologist.2018-0271] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2018] [Revised: 11/19/2018] [Accepted: 11/21/2018] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND BRAF and MEK inhibitors are approved for BRAF V600-mutated advanced melanoma, with response rates of up to 70%. Responses to targeted therapies have also been observed for diverse non-V600 BRAF alterations. Thus, sensitive, accurate, and broad detection of BRAF alterations is critical to match patients with available targeted therapies. MATERIALS AND METHODS Pathology reports were reviewed for 385 consecutive melanoma cases with BRAF mutations or rearrangements identified using a hybrid capture-based next-generation sequencing comprehensive genomic profiling (CGP) assay during the course of clinical care. RESULTS Records of prior BRAF molecular testing were available for 79 (21%) cases. Of cases with BRAF V600 mutations, 11/57 (19%) with available data were negative by prior BRAF testing. Prior negative BRAF results were also identified in 16/20 (80%) cases with non-V600 mutations, 2 of which harbored multiple BRAF alterations, and in 2/2 (100%) cases with activating BRAF fusions. Clinical outcomes for a subset of patients are presented. CONCLUSION CGP identifies diverse activating BRAF alterations in a significant fraction of cases with prior negative testing. Given the proven clinical benefit of BRAF/MEK inhibitors in BRAF-mutated melanoma, CGP should be considered for patients with metastatic melanoma, particularly if other testing is negative. IMPLICATIONS FOR PRACTICE Published guidelines for melanoma treatment recommend BRAF mutational analysis, but little guidance is provided as to selection criteria for testing methodologies, or as to clinical implications for non-V600 alterations. This study found that hybrid capture-based next-generation sequencing can detect BRAF alterations in samples from a significant fraction of patients with advanced melanoma with prior negative BRAF results. This study highlights the need for oncologists and pathologists to be critically aware of coverage and sensitivity limitations of various assays, particularly regarding non-V600E alterations, of which many are potentially targetable.
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Affiliation(s)
- Lise Boussemart
- Department of Dermatology, Pontchaillou Hospital, CHU de Rennes, Rennes, France
- University of Rennes, CNRS, IGDR, UMR 6290, Rennes, France
| | - Annie Nelson
- Foundation Medicine, Inc., Cambridge, Massachusetts, USA
| | | | - Jeffrey S Ross
- Foundation Medicine, Inc., Cambridge, Massachusetts, USA
- Department of Pathology, SUNY Upstate Medical University, Syracuse, New York, USA
| | - Jeffrey Sosman
- Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois, USA
| | - Janice Mehnert
- Department of Medicine, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey, USA
| | - Gregory Daniels
- Moores Cancer Center, University of California San Diego, La Jolla, California, USA
| | - Kari Kendra
- The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA
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44
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Kim KB, Semrad T, Schrock AB, Ali SM, Ross JS, Singer M, Kashani-Sabet M. Significant Clinical Response to a MEK Inhibitor Therapy in a Patient With Metastatic Melanoma Harboring an RAF1 Fusion. JCO Precis Oncol 2018; 2:1-6. [PMID: 35135096 DOI: 10.1200/po.17.00138] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Affiliation(s)
- Kevin B Kim
- Kevin B. Kim, Mark Singer, and Mohammed Kashani-Sabet, California Pacific Medical Center Research Institute, San Francisco; Thomas Semrad, Gene Upshaw Memorial Tahoe Forest Cancer Center, Truckee, CA; Alexa B. Schrock, Siraj M. Ali, and Jeffrey S. Ross, Foundation Medicine, Cambridge, MA; and Jeffrey S. Ross, Albany Medical College, Albany, NY
| | - Thomas Semrad
- Kevin B. Kim, Mark Singer, and Mohammed Kashani-Sabet, California Pacific Medical Center Research Institute, San Francisco; Thomas Semrad, Gene Upshaw Memorial Tahoe Forest Cancer Center, Truckee, CA; Alexa B. Schrock, Siraj M. Ali, and Jeffrey S. Ross, Foundation Medicine, Cambridge, MA; and Jeffrey S. Ross, Albany Medical College, Albany, NY
| | - Alexa B Schrock
- Kevin B. Kim, Mark Singer, and Mohammed Kashani-Sabet, California Pacific Medical Center Research Institute, San Francisco; Thomas Semrad, Gene Upshaw Memorial Tahoe Forest Cancer Center, Truckee, CA; Alexa B. Schrock, Siraj M. Ali, and Jeffrey S. Ross, Foundation Medicine, Cambridge, MA; and Jeffrey S. Ross, Albany Medical College, Albany, NY
| | - Siraj M Ali
- Kevin B. Kim, Mark Singer, and Mohammed Kashani-Sabet, California Pacific Medical Center Research Institute, San Francisco; Thomas Semrad, Gene Upshaw Memorial Tahoe Forest Cancer Center, Truckee, CA; Alexa B. Schrock, Siraj M. Ali, and Jeffrey S. Ross, Foundation Medicine, Cambridge, MA; and Jeffrey S. Ross, Albany Medical College, Albany, NY
| | - Jeffrey S Ross
- Kevin B. Kim, Mark Singer, and Mohammed Kashani-Sabet, California Pacific Medical Center Research Institute, San Francisco; Thomas Semrad, Gene Upshaw Memorial Tahoe Forest Cancer Center, Truckee, CA; Alexa B. Schrock, Siraj M. Ali, and Jeffrey S. Ross, Foundation Medicine, Cambridge, MA; and Jeffrey S. Ross, Albany Medical College, Albany, NY
| | - Mark Singer
- Kevin B. Kim, Mark Singer, and Mohammed Kashani-Sabet, California Pacific Medical Center Research Institute, San Francisco; Thomas Semrad, Gene Upshaw Memorial Tahoe Forest Cancer Center, Truckee, CA; Alexa B. Schrock, Siraj M. Ali, and Jeffrey S. Ross, Foundation Medicine, Cambridge, MA; and Jeffrey S. Ross, Albany Medical College, Albany, NY
| | - Mohammed Kashani-Sabet
- Kevin B. Kim, Mark Singer, and Mohammed Kashani-Sabet, California Pacific Medical Center Research Institute, San Francisco; Thomas Semrad, Gene Upshaw Memorial Tahoe Forest Cancer Center, Truckee, CA; Alexa B. Schrock, Siraj M. Ali, and Jeffrey S. Ross, Foundation Medicine, Cambridge, MA; and Jeffrey S. Ross, Albany Medical College, Albany, NY
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45
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Turner JA, Bemis JGT, Bagby SM, Capasso A, Yacob BW, Chimed TS, Van Gulick R, Lee H, Tobin R, Tentler JJ, Pitts T, McCarter M, Robinson WA, Couts KL. BRAF fusions identified in melanomas have variable treatment responses and phenotypes. Oncogene 2018; 38:1296-1308. [PMID: 30254212 DOI: 10.1038/s41388-018-0514-7] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Revised: 08/09/2018] [Accepted: 08/10/2018] [Indexed: 12/13/2022]
Abstract
Oncogenic BRAF fusions have emerged as an alternate mechanism for BRAF activation in melanomas and other cancers. A number of BRAF fusions with different 5' gene partners and BRAF exon breakpoints have been described, but the effects of different partners and breakpoints on cancer phenotypes and treatment responses has not been well characterized. Targeted RNA sequencing was used to screen 60 melanoma patient-derived xenograft (PDX) models for BRAF fusions. We identified three unique BRAF fusions, including a novel SEPT3-BRAF fusion, occurring in four tumors (4/60, 6.7%), all of which were "pan-negative" (lacking other common mutations) (4/18, 22.2%). The BRAF fusion PDX models showed variable growth rates and responses to MAPK inhibitors in vivo. Overexpression of BRAF fusions identified in our study, as well as other BRAF fusions previously identified in melanomas, resulted in a high degree of variability in 2D proliferation and 3D invasion between the different fusions. While exogenously expressed BRAF fusions all responded to MAPK inhibition in vitro, we observed potential differences in signaling and feedback mechanisms. In summary, BRAF fusions are actionable therapeutic targets, however there are significant differences in phenotypes, treatment responses, and signaling which may be clinically relevant.
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Affiliation(s)
- Jacqueline A Turner
- Division of Medical Oncology, Department of Medicine, University of Colorado Denver, Aurora, CO, USA
| | - Judson G T Bemis
- Division of Medical Oncology, Department of Medicine, University of Colorado Denver, Aurora, CO, USA
| | - Stacey M Bagby
- Division of Medical Oncology, Department of Medicine, University of Colorado Denver, Aurora, CO, USA
| | - Anna Capasso
- Division of Medical Oncology, Department of Medicine, University of Colorado Denver, Aurora, CO, USA
| | - Betelehem W Yacob
- Division of Medical Oncology, Department of Medicine, University of Colorado Denver, Aurora, CO, USA
| | - Tugs-Saikhan Chimed
- Division of Medical Oncology, Department of Medicine, University of Colorado Denver, Aurora, CO, USA
| | - Robert Van Gulick
- Division of Medical Oncology, Department of Medicine, University of Colorado Denver, Aurora, CO, USA
| | - Hannah Lee
- Division of Medical Oncology, Department of Medicine, University of Colorado Denver, Aurora, CO, USA.,Department of Medicine, Internal Medicine Residency Training Program, University of Colorado Denver, Aurora, CO, USA
| | - Richard Tobin
- Division Surgical Oncology, Department of Surgery, University of Colorado Denver, Aurora, CO, USA
| | - John J Tentler
- Division of Medical Oncology, Department of Medicine, University of Colorado Denver, Aurora, CO, USA
| | - Todd Pitts
- Division of Medical Oncology, Department of Medicine, University of Colorado Denver, Aurora, CO, USA
| | - Martin McCarter
- Division Surgical Oncology, Department of Surgery, University of Colorado Denver, Aurora, CO, USA
| | - William A Robinson
- Division of Medical Oncology, Department of Medicine, University of Colorado Denver, Aurora, CO, USA
| | - Kasey L Couts
- Division of Medical Oncology, Department of Medicine, University of Colorado Denver, Aurora, CO, USA.
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46
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Davis EJ, Johnson DB, Sosman JA, Chandra S. Melanoma: What do all the mutations mean? Cancer 2018; 124:3490-3499. [PMID: 29663336 PMCID: PMC6191351 DOI: 10.1002/cncr.31345] [Citation(s) in RCA: 129] [Impact Index Per Article: 18.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2017] [Revised: 02/06/2018] [Accepted: 02/13/2018] [Indexed: 12/28/2022]
Abstract
Melanoma is one of the most highly mutated malignancies, largely as a function of its generation through ultraviolet light and other mutational processes. The wide array of mutations in both "driver" and "passenger" genes can present a confusing array of data for practitioners, particularly within the context of the recent revolutions in targeted and immune therapy. Although mutations in BRAF V600 clearly confer sensitivity to BRAF and mitogen-activated protein kinase kinase (MEK) inhibitors, the clinical implications of most other mutations are less often discussed and understood. In this review, we provide an overview of the high-frequency genomic alterations and their prognostic and therapeutic relevance in melanoma.
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Affiliation(s)
- Elizabeth J. Davis
- Department of Medicine, Vanderbilt University Medical Center and Vanderbilt Ingram Cancer Center
| | - Douglas B. Johnson
- Department of Medicine, Vanderbilt University Medical Center and Vanderbilt Ingram Cancer Center
| | - Jeffrey A. Sosman
- Department of Medicine, Feinberg School of Medicine and Robert H. Lurie Comprehensive Cancer Center
| | - Sunandana Chandra
- Department of Medicine, Feinberg School of Medicine and Robert H. Lurie Comprehensive Cancer Center
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47
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Abstract
Introduction Breakthroughs in targeted therapy have significantly improved outcomes for many patients with advanced melanoma, including those with BRAFV600 mutant disease. Targeted therapy for BRAFV600-mutant metastatic melanoma includes combinations of BRAF inhibitors and MEK inhibitors, which improve response rates and prolong progression-free survival (PFS) and overall survival (OS) in these patients. However, while durable responses have been observed, many patients develop acquired resistance to these drugs. Areas covered Recent clinical trial updates and ongoing studies with targeted therapy for BRAF-V600 mutant melanoma are reviewed. Expert opinion Although BRAF targeted therapy remains an effective treatment for BRAF-mutant for melanoma, ongoing trials are exploring combinations with other targeted therapeutics and immunotherapeutics to determine whether tumor responses can be prolonged, and these drugs are increasingly utilized in the neoadjuvant and adjuvant settings.
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Affiliation(s)
- Zeynep Eroglu
- The Department of Cutaneous Oncology, Moffitt Cancer Center & Research Institute, 10920 McKinley Dr, Tampa, FL, USA
| | - Alpaslan Ozgun
- The Department of Cutaneous Oncology, Moffitt Cancer Center & Research Institute, 10920 McKinley Dr, Tampa, FL, USA
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48
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Johnson DB, Childress MA, Chalmers ZR, Frampton GM, Ali SM, Rubinstein SM, Fabrizio D, Ross JS, Balasubramanian S, Miller VA, Stephens PJ, Sosman JA, Lovly CM. BRAF internal deletions and resistance to BRAF/MEK inhibitor therapy. Pigment Cell Melanoma Res 2018; 31:432-436. [PMID: 29171936 PMCID: PMC5889338 DOI: 10.1111/pcmr.12674] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2017] [Accepted: 11/14/2017] [Indexed: 11/29/2022]
Abstract
BRAF and MEK inhibitors have improved clinical outcomes in advanced, BRAFV600 -mutated melanomas. Acquired resistance occurs in most patients, with numerous and diverse drivers. We obtained pretreatment and progression biopsies from a patient who progressed on dabrafenib and trametinib. In addition to a preserved BRAFV600E mutation, an internal deletion (rearrangement) of BRAF was observed in the progression sample. This deletion involved exons 2-8, which includes the Ras-binding domain, and is analogous to previously documented BRAF fusions and splice variants known to reactivate RAS-RAF-MEK-ERK signaling. In a large cohort of melanomas, 10 additional internal deletions were identified (0.4% of all melanomas; nine of which had concurrent BRAF mutations), as well as sporadically in other tumor types. Thus, we describe a novel mechanism of resistance to BRAF and MEK inhibition.
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Affiliation(s)
- Douglas B Johnson
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.,Department of Medicine, Vanderbilt Ingram Cancer Center, Nashville, TN, USA
| | - Merrida A Childress
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.,Department of Medicine, Vanderbilt Ingram Cancer Center, Nashville, TN, USA.,Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA.,Department of Cancer Biology, Vanderbilt Ingram Cancer Center, Nashville, TN, USA
| | | | | | - Siraj M Ali
- Foundation Medicine Inc., Cambridge, MA, USA
| | - Samuel M Rubinstein
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.,Department of Medicine, Vanderbilt Ingram Cancer Center, Nashville, TN, USA
| | | | | | | | | | | | - Jeffrey A Sosman
- Northwestern University Medical Center, Chicago, IL, USA.,Robert H. Lurie Comprehensive Cancer Center, Chicago, IL, USA
| | - Christine M Lovly
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.,Department of Medicine, Vanderbilt Ingram Cancer Center, Nashville, TN, USA.,Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA.,Department of Cancer Biology, Vanderbilt Ingram Cancer Center, Nashville, TN, USA
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Sheikine Y, Pavlick D, Klempner SJ, Trabucco SE, Chung JH, Rosenzweig M, Wang K, Velcheti V, Frampton GM, Peled N, Murray M, Chae YK, Albacker LA, Gay L, Husain H, Suh JH, Millis SZ, Reddy VP, Elvin JA, Hartmaier RJ, Dowlati A, Stephens P, Ross JS, Bivona TG, Miller VA, Ganesan S, Schrock AB, Ou SHI, Ali SM. BRAF in Lung Cancers: Analysis of Patient Cases Reveals Recurrent BRAF Mutations, Fusions, Kinase Duplications, and Concurrent Alterations. JCO Precis Oncol 2018; 2:1700172. [PMID: 32913992 DOI: 10.1200/po.17.00172] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Purpose Dabrafenib and trametinib are approved for the management of advanced non-small-cell lung cancers (NSCLCs) that harbor BRAF V600E mutations. Small series and pan-cancer analyses have identified non-V600 alterations as therapeutic targets. We sought to examine a large genomic data set to comprehensively characterize non-V600 BRAF alterations in lung cancer. Patients and Methods A total of 23,396 patients with lung cancer provided data to assay with comprehensive genomic profiling. Data were reviewed for predicted pathogenic BRAF base substitutions, short insertions and deletions, copy number changes, and rearrangements. Results Adenocarcinomas represented 65% of the occurrences; NSCLC not otherwise specified (NOS), 15%; squamous cell carcinoma, 12%; and small-cell lung carcinoma, 5%. BRAF was altered in 4.5% (1,048 of 23,396) of all tumors; 37.4% (n = 397) were BRAF V600E, 38% were BRAF non-V600E activating mutations, and 18% were BRAF inactivating. Rearrangements were observed at a frequency of 4.3% and consisted of N-terminal deletions (NTDs; 0.75%), kinase domain duplications (KDDs; 0.75%), and BRAF fusions (2.8%). The fusions involved three recurrent fusion partners: ARMC10, DOCK4, and TRIM24. BRAF V600E was associated with co-occurrence of SETD2 alterations, but other BRAF alterations were not and were instead associated with CDKN2A, TP53, and STK11 alterations (P < .05). Potential mechanisms of acquired resistance to BRAF V600E inhibition are demonstrated. Conclusion This series characterized the frequent occurrence (4.4%) of BRAF alterations in lung cancers. Recurrent BRAF alterations in NSCLC adenocarcinoma are comparable to the frequency of other NSCLC oncogenic drivers, such as ALK, and exceed that of ROS1 or RET. This work supports a broad profiling approach in lung cancers and suggests that non-V600E BRAF alterations represent a subgroup of lung cancers in which targeted therapy should be considered.
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Affiliation(s)
- Yuri Sheikine
- , Vancouver General Hospital, Vancouver, British Columbia, Canada; , , , , , , , , , , , , , , , , , , and , Foundation Medicine, Cambridge, MA; , The Angeles Clinic and Research Institute and Cedars-Sinai Medical Center, Los Angeles; , University of California San Diego, San Diego; , University of California, San Francisco, San Francisco; and , University of California, Irvine, Medical Center, Irvine, CA; , Cleveland Clinic; and , University Hospitals Cleveland Medical Center and Case Western Reserve University, Cleveland, OH; , Soroka Medical Center and Ben-Gurion University, Beer-Sheve, Israel; , Northwestern University Feinberg School of Medicine Northwestern Medical Center, Chicago, IL; and , Cancer Institute of New Jersey, New Brunswick, NJ
| | - Dean Pavlick
- , Vancouver General Hospital, Vancouver, British Columbia, Canada; , , , , , , , , , , , , , , , , , , and , Foundation Medicine, Cambridge, MA; , The Angeles Clinic and Research Institute and Cedars-Sinai Medical Center, Los Angeles; , University of California San Diego, San Diego; , University of California, San Francisco, San Francisco; and , University of California, Irvine, Medical Center, Irvine, CA; , Cleveland Clinic; and , University Hospitals Cleveland Medical Center and Case Western Reserve University, Cleveland, OH; , Soroka Medical Center and Ben-Gurion University, Beer-Sheve, Israel; , Northwestern University Feinberg School of Medicine Northwestern Medical Center, Chicago, IL; and , Cancer Institute of New Jersey, New Brunswick, NJ
| | - Samuel J Klempner
- , Vancouver General Hospital, Vancouver, British Columbia, Canada; , , , , , , , , , , , , , , , , , , and , Foundation Medicine, Cambridge, MA; , The Angeles Clinic and Research Institute and Cedars-Sinai Medical Center, Los Angeles; , University of California San Diego, San Diego; , University of California, San Francisco, San Francisco; and , University of California, Irvine, Medical Center, Irvine, CA; , Cleveland Clinic; and , University Hospitals Cleveland Medical Center and Case Western Reserve University, Cleveland, OH; , Soroka Medical Center and Ben-Gurion University, Beer-Sheve, Israel; , Northwestern University Feinberg School of Medicine Northwestern Medical Center, Chicago, IL; and , Cancer Institute of New Jersey, New Brunswick, NJ
| | - Sally E Trabucco
- , Vancouver General Hospital, Vancouver, British Columbia, Canada; , , , , , , , , , , , , , , , , , , and , Foundation Medicine, Cambridge, MA; , The Angeles Clinic and Research Institute and Cedars-Sinai Medical Center, Los Angeles; , University of California San Diego, San Diego; , University of California, San Francisco, San Francisco; and , University of California, Irvine, Medical Center, Irvine, CA; , Cleveland Clinic; and , University Hospitals Cleveland Medical Center and Case Western Reserve University, Cleveland, OH; , Soroka Medical Center and Ben-Gurion University, Beer-Sheve, Israel; , Northwestern University Feinberg School of Medicine Northwestern Medical Center, Chicago, IL; and , Cancer Institute of New Jersey, New Brunswick, NJ
| | - Jon H Chung
- , Vancouver General Hospital, Vancouver, British Columbia, Canada; , , , , , , , , , , , , , , , , , , and , Foundation Medicine, Cambridge, MA; , The Angeles Clinic and Research Institute and Cedars-Sinai Medical Center, Los Angeles; , University of California San Diego, San Diego; , University of California, San Francisco, San Francisco; and , University of California, Irvine, Medical Center, Irvine, CA; , Cleveland Clinic; and , University Hospitals Cleveland Medical Center and Case Western Reserve University, Cleveland, OH; , Soroka Medical Center and Ben-Gurion University, Beer-Sheve, Israel; , Northwestern University Feinberg School of Medicine Northwestern Medical Center, Chicago, IL; and , Cancer Institute of New Jersey, New Brunswick, NJ
| | - Mark Rosenzweig
- , Vancouver General Hospital, Vancouver, British Columbia, Canada; , , , , , , , , , , , , , , , , , , and , Foundation Medicine, Cambridge, MA; , The Angeles Clinic and Research Institute and Cedars-Sinai Medical Center, Los Angeles; , University of California San Diego, San Diego; , University of California, San Francisco, San Francisco; and , University of California, Irvine, Medical Center, Irvine, CA; , Cleveland Clinic; and , University Hospitals Cleveland Medical Center and Case Western Reserve University, Cleveland, OH; , Soroka Medical Center and Ben-Gurion University, Beer-Sheve, Israel; , Northwestern University Feinberg School of Medicine Northwestern Medical Center, Chicago, IL; and , Cancer Institute of New Jersey, New Brunswick, NJ
| | - Kai Wang
- , Vancouver General Hospital, Vancouver, British Columbia, Canada; , , , , , , , , , , , , , , , , , , and , Foundation Medicine, Cambridge, MA; , The Angeles Clinic and Research Institute and Cedars-Sinai Medical Center, Los Angeles; , University of California San Diego, San Diego; , University of California, San Francisco, San Francisco; and , University of California, Irvine, Medical Center, Irvine, CA; , Cleveland Clinic; and , University Hospitals Cleveland Medical Center and Case Western Reserve University, Cleveland, OH; , Soroka Medical Center and Ben-Gurion University, Beer-Sheve, Israel; , Northwestern University Feinberg School of Medicine Northwestern Medical Center, Chicago, IL; and , Cancer Institute of New Jersey, New Brunswick, NJ
| | - Vamsidhar Velcheti
- , Vancouver General Hospital, Vancouver, British Columbia, Canada; , , , , , , , , , , , , , , , , , , and , Foundation Medicine, Cambridge, MA; , The Angeles Clinic and Research Institute and Cedars-Sinai Medical Center, Los Angeles; , University of California San Diego, San Diego; , University of California, San Francisco, San Francisco; and , University of California, Irvine, Medical Center, Irvine, CA; , Cleveland Clinic; and , University Hospitals Cleveland Medical Center and Case Western Reserve University, Cleveland, OH; , Soroka Medical Center and Ben-Gurion University, Beer-Sheve, Israel; , Northwestern University Feinberg School of Medicine Northwestern Medical Center, Chicago, IL; and , Cancer Institute of New Jersey, New Brunswick, NJ
| | - Garrett M Frampton
- , Vancouver General Hospital, Vancouver, British Columbia, Canada; , , , , , , , , , , , , , , , , , , and , Foundation Medicine, Cambridge, MA; , The Angeles Clinic and Research Institute and Cedars-Sinai Medical Center, Los Angeles; , University of California San Diego, San Diego; , University of California, San Francisco, San Francisco; and , University of California, Irvine, Medical Center, Irvine, CA; , Cleveland Clinic; and , University Hospitals Cleveland Medical Center and Case Western Reserve University, Cleveland, OH; , Soroka Medical Center and Ben-Gurion University, Beer-Sheve, Israel; , Northwestern University Feinberg School of Medicine Northwestern Medical Center, Chicago, IL; and , Cancer Institute of New Jersey, New Brunswick, NJ
| | - Nir Peled
- , Vancouver General Hospital, Vancouver, British Columbia, Canada; , , , , , , , , , , , , , , , , , , and , Foundation Medicine, Cambridge, MA; , The Angeles Clinic and Research Institute and Cedars-Sinai Medical Center, Los Angeles; , University of California San Diego, San Diego; , University of California, San Francisco, San Francisco; and , University of California, Irvine, Medical Center, Irvine, CA; , Cleveland Clinic; and , University Hospitals Cleveland Medical Center and Case Western Reserve University, Cleveland, OH; , Soroka Medical Center and Ben-Gurion University, Beer-Sheve, Israel; , Northwestern University Feinberg School of Medicine Northwestern Medical Center, Chicago, IL; and , Cancer Institute of New Jersey, New Brunswick, NJ
| | - Molly Murray
- , Vancouver General Hospital, Vancouver, British Columbia, Canada; , , , , , , , , , , , , , , , , , , and , Foundation Medicine, Cambridge, MA; , The Angeles Clinic and Research Institute and Cedars-Sinai Medical Center, Los Angeles; , University of California San Diego, San Diego; , University of California, San Francisco, San Francisco; and , University of California, Irvine, Medical Center, Irvine, CA; , Cleveland Clinic; and , University Hospitals Cleveland Medical Center and Case Western Reserve University, Cleveland, OH; , Soroka Medical Center and Ben-Gurion University, Beer-Sheve, Israel; , Northwestern University Feinberg School of Medicine Northwestern Medical Center, Chicago, IL; and , Cancer Institute of New Jersey, New Brunswick, NJ
| | - Young Kwang Chae
- , Vancouver General Hospital, Vancouver, British Columbia, Canada; , , , , , , , , , , , , , , , , , , and , Foundation Medicine, Cambridge, MA; , The Angeles Clinic and Research Institute and Cedars-Sinai Medical Center, Los Angeles; , University of California San Diego, San Diego; , University of California, San Francisco, San Francisco; and , University of California, Irvine, Medical Center, Irvine, CA; , Cleveland Clinic; and , University Hospitals Cleveland Medical Center and Case Western Reserve University, Cleveland, OH; , Soroka Medical Center and Ben-Gurion University, Beer-Sheve, Israel; , Northwestern University Feinberg School of Medicine Northwestern Medical Center, Chicago, IL; and , Cancer Institute of New Jersey, New Brunswick, NJ
| | - Lee A Albacker
- , Vancouver General Hospital, Vancouver, British Columbia, Canada; , , , , , , , , , , , , , , , , , , and , Foundation Medicine, Cambridge, MA; , The Angeles Clinic and Research Institute and Cedars-Sinai Medical Center, Los Angeles; , University of California San Diego, San Diego; , University of California, San Francisco, San Francisco; and , University of California, Irvine, Medical Center, Irvine, CA; , Cleveland Clinic; and , University Hospitals Cleveland Medical Center and Case Western Reserve University, Cleveland, OH; , Soroka Medical Center and Ben-Gurion University, Beer-Sheve, Israel; , Northwestern University Feinberg School of Medicine Northwestern Medical Center, Chicago, IL; and , Cancer Institute of New Jersey, New Brunswick, NJ
| | - Laurie Gay
- , Vancouver General Hospital, Vancouver, British Columbia, Canada; , , , , , , , , , , , , , , , , , , and , Foundation Medicine, Cambridge, MA; , The Angeles Clinic and Research Institute and Cedars-Sinai Medical Center, Los Angeles; , University of California San Diego, San Diego; , University of California, San Francisco, San Francisco; and , University of California, Irvine, Medical Center, Irvine, CA; , Cleveland Clinic; and , University Hospitals Cleveland Medical Center and Case Western Reserve University, Cleveland, OH; , Soroka Medical Center and Ben-Gurion University, Beer-Sheve, Israel; , Northwestern University Feinberg School of Medicine Northwestern Medical Center, Chicago, IL; and , Cancer Institute of New Jersey, New Brunswick, NJ
| | - Hatim Husain
- , Vancouver General Hospital, Vancouver, British Columbia, Canada; , , , , , , , , , , , , , , , , , , and , Foundation Medicine, Cambridge, MA; , The Angeles Clinic and Research Institute and Cedars-Sinai Medical Center, Los Angeles; , University of California San Diego, San Diego; , University of California, San Francisco, San Francisco; and , University of California, Irvine, Medical Center, Irvine, CA; , Cleveland Clinic; and , University Hospitals Cleveland Medical Center and Case Western Reserve University, Cleveland, OH; , Soroka Medical Center and Ben-Gurion University, Beer-Sheve, Israel; , Northwestern University Feinberg School of Medicine Northwestern Medical Center, Chicago, IL; and , Cancer Institute of New Jersey, New Brunswick, NJ
| | - James H Suh
- , Vancouver General Hospital, Vancouver, British Columbia, Canada; , , , , , , , , , , , , , , , , , , and , Foundation Medicine, Cambridge, MA; , The Angeles Clinic and Research Institute and Cedars-Sinai Medical Center, Los Angeles; , University of California San Diego, San Diego; , University of California, San Francisco, San Francisco; and , University of California, Irvine, Medical Center, Irvine, CA; , Cleveland Clinic; and , University Hospitals Cleveland Medical Center and Case Western Reserve University, Cleveland, OH; , Soroka Medical Center and Ben-Gurion University, Beer-Sheve, Israel; , Northwestern University Feinberg School of Medicine Northwestern Medical Center, Chicago, IL; and , Cancer Institute of New Jersey, New Brunswick, NJ
| | - Sherri Z Millis
- , Vancouver General Hospital, Vancouver, British Columbia, Canada; , , , , , , , , , , , , , , , , , , and , Foundation Medicine, Cambridge, MA; , The Angeles Clinic and Research Institute and Cedars-Sinai Medical Center, Los Angeles; , University of California San Diego, San Diego; , University of California, San Francisco, San Francisco; and , University of California, Irvine, Medical Center, Irvine, CA; , Cleveland Clinic; and , University Hospitals Cleveland Medical Center and Case Western Reserve University, Cleveland, OH; , Soroka Medical Center and Ben-Gurion University, Beer-Sheve, Israel; , Northwestern University Feinberg School of Medicine Northwestern Medical Center, Chicago, IL; and , Cancer Institute of New Jersey, New Brunswick, NJ
| | - Venkataprasanth P Reddy
- , Vancouver General Hospital, Vancouver, British Columbia, Canada; , , , , , , , , , , , , , , , , , , and , Foundation Medicine, Cambridge, MA; , The Angeles Clinic and Research Institute and Cedars-Sinai Medical Center, Los Angeles; , University of California San Diego, San Diego; , University of California, San Francisco, San Francisco; and , University of California, Irvine, Medical Center, Irvine, CA; , Cleveland Clinic; and , University Hospitals Cleveland Medical Center and Case Western Reserve University, Cleveland, OH; , Soroka Medical Center and Ben-Gurion University, Beer-Sheve, Israel; , Northwestern University Feinberg School of Medicine Northwestern Medical Center, Chicago, IL; and , Cancer Institute of New Jersey, New Brunswick, NJ
| | - Julia A Elvin
- , Vancouver General Hospital, Vancouver, British Columbia, Canada; , , , , , , , , , , , , , , , , , , and , Foundation Medicine, Cambridge, MA; , The Angeles Clinic and Research Institute and Cedars-Sinai Medical Center, Los Angeles; , University of California San Diego, San Diego; , University of California, San Francisco, San Francisco; and , University of California, Irvine, Medical Center, Irvine, CA; , Cleveland Clinic; and , University Hospitals Cleveland Medical Center and Case Western Reserve University, Cleveland, OH; , Soroka Medical Center and Ben-Gurion University, Beer-Sheve, Israel; , Northwestern University Feinberg School of Medicine Northwestern Medical Center, Chicago, IL; and , Cancer Institute of New Jersey, New Brunswick, NJ
| | - Ryan J Hartmaier
- , Vancouver General Hospital, Vancouver, British Columbia, Canada; , , , , , , , , , , , , , , , , , , and , Foundation Medicine, Cambridge, MA; , The Angeles Clinic and Research Institute and Cedars-Sinai Medical Center, Los Angeles; , University of California San Diego, San Diego; , University of California, San Francisco, San Francisco; and , University of California, Irvine, Medical Center, Irvine, CA; , Cleveland Clinic; and , University Hospitals Cleveland Medical Center and Case Western Reserve University, Cleveland, OH; , Soroka Medical Center and Ben-Gurion University, Beer-Sheve, Israel; , Northwestern University Feinberg School of Medicine Northwestern Medical Center, Chicago, IL; and , Cancer Institute of New Jersey, New Brunswick, NJ
| | - Afshin Dowlati
- , Vancouver General Hospital, Vancouver, British Columbia, Canada; , , , , , , , , , , , , , , , , , , and , Foundation Medicine, Cambridge, MA; , The Angeles Clinic and Research Institute and Cedars-Sinai Medical Center, Los Angeles; , University of California San Diego, San Diego; , University of California, San Francisco, San Francisco; and , University of California, Irvine, Medical Center, Irvine, CA; , Cleveland Clinic; and , University Hospitals Cleveland Medical Center and Case Western Reserve University, Cleveland, OH; , Soroka Medical Center and Ben-Gurion University, Beer-Sheve, Israel; , Northwestern University Feinberg School of Medicine Northwestern Medical Center, Chicago, IL; and , Cancer Institute of New Jersey, New Brunswick, NJ
| | - Phil Stephens
- , Vancouver General Hospital, Vancouver, British Columbia, Canada; , , , , , , , , , , , , , , , , , , and , Foundation Medicine, Cambridge, MA; , The Angeles Clinic and Research Institute and Cedars-Sinai Medical Center, Los Angeles; , University of California San Diego, San Diego; , University of California, San Francisco, San Francisco; and , University of California, Irvine, Medical Center, Irvine, CA; , Cleveland Clinic; and , University Hospitals Cleveland Medical Center and Case Western Reserve University, Cleveland, OH; , Soroka Medical Center and Ben-Gurion University, Beer-Sheve, Israel; , Northwestern University Feinberg School of Medicine Northwestern Medical Center, Chicago, IL; and , Cancer Institute of New Jersey, New Brunswick, NJ
| | - Jeffrey S Ross
- , Vancouver General Hospital, Vancouver, British Columbia, Canada; , , , , , , , , , , , , , , , , , , and , Foundation Medicine, Cambridge, MA; , The Angeles Clinic and Research Institute and Cedars-Sinai Medical Center, Los Angeles; , University of California San Diego, San Diego; , University of California, San Francisco, San Francisco; and , University of California, Irvine, Medical Center, Irvine, CA; , Cleveland Clinic; and , University Hospitals Cleveland Medical Center and Case Western Reserve University, Cleveland, OH; , Soroka Medical Center and Ben-Gurion University, Beer-Sheve, Israel; , Northwestern University Feinberg School of Medicine Northwestern Medical Center, Chicago, IL; and , Cancer Institute of New Jersey, New Brunswick, NJ
| | - Trever G Bivona
- , Vancouver General Hospital, Vancouver, British Columbia, Canada; , , , , , , , , , , , , , , , , , , and , Foundation Medicine, Cambridge, MA; , The Angeles Clinic and Research Institute and Cedars-Sinai Medical Center, Los Angeles; , University of California San Diego, San Diego; , University of California, San Francisco, San Francisco; and , University of California, Irvine, Medical Center, Irvine, CA; , Cleveland Clinic; and , University Hospitals Cleveland Medical Center and Case Western Reserve University, Cleveland, OH; , Soroka Medical Center and Ben-Gurion University, Beer-Sheve, Israel; , Northwestern University Feinberg School of Medicine Northwestern Medical Center, Chicago, IL; and , Cancer Institute of New Jersey, New Brunswick, NJ
| | - Vincent A Miller
- , Vancouver General Hospital, Vancouver, British Columbia, Canada; , , , , , , , , , , , , , , , , , , and , Foundation Medicine, Cambridge, MA; , The Angeles Clinic and Research Institute and Cedars-Sinai Medical Center, Los Angeles; , University of California San Diego, San Diego; , University of California, San Francisco, San Francisco; and , University of California, Irvine, Medical Center, Irvine, CA; , Cleveland Clinic; and , University Hospitals Cleveland Medical Center and Case Western Reserve University, Cleveland, OH; , Soroka Medical Center and Ben-Gurion University, Beer-Sheve, Israel; , Northwestern University Feinberg School of Medicine Northwestern Medical Center, Chicago, IL; and , Cancer Institute of New Jersey, New Brunswick, NJ
| | - Shridar Ganesan
- , Vancouver General Hospital, Vancouver, British Columbia, Canada; , , , , , , , , , , , , , , , , , , and , Foundation Medicine, Cambridge, MA; , The Angeles Clinic and Research Institute and Cedars-Sinai Medical Center, Los Angeles; , University of California San Diego, San Diego; , University of California, San Francisco, San Francisco; and , University of California, Irvine, Medical Center, Irvine, CA; , Cleveland Clinic; and , University Hospitals Cleveland Medical Center and Case Western Reserve University, Cleveland, OH; , Soroka Medical Center and Ben-Gurion University, Beer-Sheve, Israel; , Northwestern University Feinberg School of Medicine Northwestern Medical Center, Chicago, IL; and , Cancer Institute of New Jersey, New Brunswick, NJ
| | - Alexa B Schrock
- , Vancouver General Hospital, Vancouver, British Columbia, Canada; , , , , , , , , , , , , , , , , , , and , Foundation Medicine, Cambridge, MA; , The Angeles Clinic and Research Institute and Cedars-Sinai Medical Center, Los Angeles; , University of California San Diego, San Diego; , University of California, San Francisco, San Francisco; and , University of California, Irvine, Medical Center, Irvine, CA; , Cleveland Clinic; and , University Hospitals Cleveland Medical Center and Case Western Reserve University, Cleveland, OH; , Soroka Medical Center and Ben-Gurion University, Beer-Sheve, Israel; , Northwestern University Feinberg School of Medicine Northwestern Medical Center, Chicago, IL; and , Cancer Institute of New Jersey, New Brunswick, NJ
| | - Sai-Hong Ignatius Ou
- , Vancouver General Hospital, Vancouver, British Columbia, Canada; , , , , , , , , , , , , , , , , , , and , Foundation Medicine, Cambridge, MA; , The Angeles Clinic and Research Institute and Cedars-Sinai Medical Center, Los Angeles; , University of California San Diego, San Diego; , University of California, San Francisco, San Francisco; and , University of California, Irvine, Medical Center, Irvine, CA; , Cleveland Clinic; and , University Hospitals Cleveland Medical Center and Case Western Reserve University, Cleveland, OH; , Soroka Medical Center and Ben-Gurion University, Beer-Sheve, Israel; , Northwestern University Feinberg School of Medicine Northwestern Medical Center, Chicago, IL; and , Cancer Institute of New Jersey, New Brunswick, NJ
| | - Siraj M Ali
- , Vancouver General Hospital, Vancouver, British Columbia, Canada; , , , , , , , , , , , , , , , , , , and , Foundation Medicine, Cambridge, MA; , The Angeles Clinic and Research Institute and Cedars-Sinai Medical Center, Los Angeles; , University of California San Diego, San Diego; , University of California, San Francisco, San Francisco; and , University of California, Irvine, Medical Center, Irvine, CA; , Cleveland Clinic; and , University Hospitals Cleveland Medical Center and Case Western Reserve University, Cleveland, OH; , Soroka Medical Center and Ben-Gurion University, Beer-Sheve, Israel; , Northwestern University Feinberg School of Medicine Northwestern Medical Center, Chicago, IL; and , Cancer Institute of New Jersey, New Brunswick, NJ
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Lim HC, Montesion M, Botton T, Collisson EA, Umetsu SE, Behr SC, Gordan JD, Stephens PJ, Kelley RK. Hybrid Capture-Based Tumor Sequencing and Copy Number Analysis to Confirm Origin of Metachronous Metastases in BRCA1-Mutant Cholangiocarcinoma Harboring a Novel YWHAZ-BRAF Fusion. Oncologist 2018; 23:998-1003. [PMID: 29622700 DOI: 10.1634/theoncologist.2017-0645] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2017] [Accepted: 02/12/2018] [Indexed: 01/07/2023] Open
Abstract
Biliary tract cancers such as cholangiocarcinoma represent a heterogeneous group of cancers that can be difficult to diagnose. Recent comprehensive genomic analyses in large cholangiocarcinoma cohorts have defined important molecular subgroups within cholangiocarcinoma that may relate to anatomic location and etiology [1], [2], [3], [4] and may predict responsiveness to targeted therapies in development [5], [6], [7]. These emerging data highlight the potential for tumor genomics to inform diagnosis and treatment options in this challenging tumor type. We report the case of a patient with a germline BRCA1 mutation who presented with a cholangiocarcinoma driven by the novel YWHAZ-BRAF fusion. Hybrid capture-based DNA sequencing and copy number analysis performed as part of clinical care demonstrated that two later-occurring tumors were clonally derived from the primary cholangiocarcinoma rather than distinct new primaries, revealing an unusual pattern of late metachronous metastasis. We discuss the clinical significance of these genetic alterations and their relevance to therapeutic strategies. KEY POINTS Hybrid capture-based next-generation DNA sequencing assays can provide diagnostic clarity in patients with unusual patterns of metastasis and recurrence in which the pathologic diagnosis is ambiguous.To our knowledge, this is the first reported case of a YWHAZ-BRAF fusion in pancreaticobiliary cancer, and a very rare case of cholangiocarcinoma in the setting of a germline BRCA1 mutation.The patient's BRCA1 mutation and YWHAZ-BRAF fusion constitute potential targets for future therapy.
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Affiliation(s)
- Huat C Lim
- Department of Medicine, University of California, San Francisco, San Francisco, California, USA
| | | | - Thomas Botton
- Department of Dermatology, University of California, San Francisco, San Francisco, California, USA
- Department of Pathology, University of California, San Francisco, San Francisco, California, USA
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California, USA
| | - Eric A Collisson
- Department of Medicine, University of California, San Francisco, San Francisco, California, USA
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California, USA
| | - Sarah E Umetsu
- Department of Pathology, University of California, San Francisco, San Francisco, California, USA
| | - Spencer C Behr
- Department of Radiology, University of California, San Francisco, San Francisco, California, USA
| | - John D Gordan
- Department of Medicine, University of California, San Francisco, San Francisco, California, USA
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California, USA
| | | | - Robin K Kelley
- Department of Medicine, University of California, San Francisco, San Francisco, California, USA
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California, USA
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