|
1
|
Jang KY, Kim KM, Ha GW, Lee MR, Park HS, Chung MJ, Moon WS, Ahn AR. PD-L1 and ALK expressions in stages III and IV colorectal cancer and their correlation with clinicopathological features. Medicine (Baltimore) 2025; 104:e41228. [PMID: 40184080 PMCID: PMC11709163 DOI: 10.1097/md.0000000000041228] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2024] [Revised: 12/13/2024] [Accepted: 12/18/2024] [Indexed: 04/05/2025] Open
Abstract
Colorectal cancer (CRC) is a type of cancer with a high recurrence rate. Studies are in the progress to identify effective treatments for CRC patients. We aimed to compare the expression of programmed death-ligand 1 (PD-L1) and anaplastic lymphoma kinase (ALK) in stages III and IV CRC patients and evaluate the clinicopathological significance associated with their expression. A total of 169 stages III and IV CRC specimens was tested for ALK (D5F3) and PD-L1 (SP142 and SP263) expression using immunohistochemistry on formalin-fixed paraffin-embedded specimens. Clinicopathological characteristics were obtained through a review of the medical records and hematoxylin and eosin slides. Expression of PD-L1 SP142 and PD-L1 SP263 was detected in 17.8% and 28.4% of CRC patients, respectively. ALK D5F3 expression was detected in 4 cases. PD-L1 SP142 expression was significantly correlated with tumor site and serum carcinoembryonic antigen (CEA) level. PD-L1 SP263 expression was associated with serum tumor marker level and tumor-infiltrating lymphocytes. In univariate analysis, PD-L1 expression was correlated with shorter survival in CRC patients. PD-L1 SP263 expression was an independent indicator of shorter survival in multivariate analysis. PD-L1 expression was associated with poor prognostic factors, including shorter survival. Further investigation is needed to understand the mechanisms of the association between PD-L1 expression and unfavorable CRC prognosis.
Collapse
Affiliation(s)
- Kyu Yun Jang
- Department of Pathology, Jeonbuk National University Medical School, Research Institute of Clinical Medicine of Jeonbuk National University, Biomedical Research Institute of Jeonbuk National University Hospital, and Research Institute for Endocrine Sciences, Jeonju, Jeonbuk, Republic of Korea
| | - Kyoung Min Kim
- Department of Pathology, Jeonbuk National University Medical School, Research Institute of Clinical Medicine of Jeonbuk National University, Biomedical Research Institute of Jeonbuk National University Hospital, and Research Institute for Endocrine Sciences, Jeonju, Jeonbuk, Republic of Korea
| | - Gi Won Ha
- Department of General Surgery, Jeonbuk National University Medical School, Research Institute of Clinical Medicine of Jeonbuk National University, Biomedical Research Institute of Jeonbuk National University Hospital, and Research Institute for Endocrine Sciences, Jeonju, Jeonbuk, Republic of Korea
| | - Min Ro Lee
- Department of General Surgery, Jeonbuk National University Medical School, Research Institute of Clinical Medicine of Jeonbuk National University, Biomedical Research Institute of Jeonbuk National University Hospital, and Research Institute for Endocrine Sciences, Jeonju, Jeonbuk, Republic of Korea
| | - Ho Sung Park
- Department of Pathology, Jeonbuk National University Medical School, Research Institute of Clinical Medicine of Jeonbuk National University, Biomedical Research Institute of Jeonbuk National University Hospital, and Research Institute for Endocrine Sciences, Jeonju, Jeonbuk, Republic of Korea
| | - Myoung Ja Chung
- Department of Pathology, Jeonbuk National University Medical School, Research Institute of Clinical Medicine of Jeonbuk National University, Biomedical Research Institute of Jeonbuk National University Hospital, and Research Institute for Endocrine Sciences, Jeonju, Jeonbuk, Republic of Korea
| | - Woo Sung Moon
- Department of Pathology, Jeonbuk National University Medical School, Research Institute of Clinical Medicine of Jeonbuk National University, Biomedical Research Institute of Jeonbuk National University Hospital, and Research Institute for Endocrine Sciences, Jeonju, Jeonbuk, Republic of Korea
| | - Ae Ri Ahn
- Department of Pathology, Jeonbuk National University Medical School, Research Institute of Clinical Medicine of Jeonbuk National University, Biomedical Research Institute of Jeonbuk National University Hospital, and Research Institute for Endocrine Sciences, Jeonju, Jeonbuk, Republic of Korea
| |
Collapse
|
|
2
|
Okano S, Yamashiro Y, Onagi H, Sasa K, Hayashi T, Takahashi M, Sugimoto K, Sakamoto K, Yao T, Saito T. Tyrosine kinase alterations in colorectal cancer with emphasis on the distinct clinicopathological characteristics. Histopathology 2023; 83:733-742. [PMID: 37503542 DOI: 10.1111/his.15015] [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: 04/20/2023] [Revised: 05/31/2023] [Accepted: 07/11/2023] [Indexed: 07/29/2023]
Abstract
AIMS Tyrosine kinase (TK) alterations, such as anaplastic lymphoma kinase (ALK) fusion, neurotrophic tyrosine receptor kinase (NTRK) fusion, c-ros oncogene 1 (ROS1) fusion and mesenchymal-epithelial transition factor (MET) exon 14 skipping, have been reported in colorectal cancers (CRC). We have previously reported CRCs with NTRK fusion among our cohort. However, their clinicopathological features have not been fully elucidated. METHODS AND RESULTS Tissue microarray (TMA)-based immunohistochemistry (IHC) was performed on 951 CRC lesions from 944 patients. IHC was evaluated as positive or negative for ALK and ROS1 and 0 to 3+ for c-MET. For ALK and ROS1 IHC-positive cases, RNA-based imbalanced gene expression assays, Archer FusionPlex assays and reverse transcription-polymerase chain reaction (RT-PCR) followed by Sanger sequencing were performed. For c-MET IHC 3+ cases, RT-PCR followed by Sanger sequencing were performed. ALK IHC was positive in three cases (0.2%) and all showed imbalanced ALK gene expression. The following ALK fusions were confirmed: EML4 (exon 21)::ALK (exon 20), EML4 (exon 6)::ALK (exon 19) and HMBOX1 (exon 6)::ALK (exon 20). Two showed microsatellite instability-high/mismatch repair (MMR)-deficient, and all were located in the right colon. ROS1 IHC was positive in one case; however, imbalanced expression and ROS1 fusion was negative. Forty-two cases (4.4%) showed c-MET IHC3+. MET exon 14 skipping was confirmed in nine cases. All cases were microsatellite stable/MMR-proficient, and eight were located in the left colon and rectum. CONCLUSIONS CRCs with these TK alterations had distinct clinicopathological features. Together with our previous study, 15 cases (1.6%) harboured targetable TK alterations (three NTRK fusion, three ALK fusion, nine MET exon 14 skipping).
Collapse
Affiliation(s)
- Soh Okano
- Department of Human Pathology, Graduate School of Medicine, Juntendo University, Tokyo, Japan
| | - Yuya Yamashiro
- Department of Human Pathology, Graduate School of Medicine, Juntendo University, Tokyo, Japan
| | - Hiroko Onagi
- Department of Human Pathology, Graduate School of Medicine, Juntendo University, Tokyo, Japan
| | - Keita Sasa
- Department of Human Pathology, Graduate School of Medicine, Juntendo University, Tokyo, Japan
- Department of Medicine for Orthopedics and Motor Organ, Graduate School of Medicine, Juntendo University, Tokyo, Japan
| | - Takuo Hayashi
- Department of Human Pathology, Graduate School of Medicine, Juntendo University, Tokyo, Japan
| | - Makoto Takahashi
- Department of Coloproctological Surgery, Graduate School of Medicine, Juntendo University, Tokyo, Japan
| | - Kiichi Sugimoto
- Department of Coloproctological Surgery, Graduate School of Medicine, Juntendo University, Tokyo, Japan
| | - Kazuhiro Sakamoto
- Department of Coloproctological Surgery, Graduate School of Medicine, Juntendo University, Tokyo, Japan
| | - Takashi Yao
- Department of Human Pathology, Graduate School of Medicine, Juntendo University, Tokyo, Japan
| | - Tsuyoshi Saito
- Department of Human Pathology, Graduate School of Medicine, Juntendo University, Tokyo, Japan
- Intractable Disease Research Center, Graduate School of Medicine, Juntendo University, Tokyo, Japan
| |
Collapse
|
|
3
|
Ukkola I, Nummela P, Kero M, Tammio H, Tuominen J, Kairisto V, Kallajoki M, Haglund C, Peltomäki P, Kytölä S, Ristimäki A. Gene fusions and oncogenic mutations in MLH1 deficient and BRAFV600E wild-type colorectal cancers. Virchows Arch 2022; 480:807-817. [PMID: 35237889 PMCID: PMC9023403 DOI: 10.1007/s00428-022-03302-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 01/19/2022] [Accepted: 02/05/2022] [Indexed: 01/09/2023]
Abstract
Gene fusions can act as oncogenic drivers and offer targets for cancer therapy. Since fusions are rare in colorectal cancer (CRC), their universal screening seems impractical. Our aim was to investigate gene fusions in 62 CRC cases with deficient MLH1 (dMLH1) and BRAFV600E wild-type (wt) status from a consecutive real-life series of 2079 CRCs. First, gene fusions were analysed using a novel FusionPlex Lung v2 RNA-based next-generation sequencing (NGS) panel, and these results were compared to a novel Idylla GeneFusion assay and pan-TRK immunohistochemistry (IHC). NGS detected seven (7/62, 11%) NTRK1 fusions (TPM3::NTRK1, PLEKHA6::NTRK1 and LMNA::NTRK1, each in two cases, and IRF2BP2::NTRK1 in one case). In addition, two ALK, four RET and seven BRAF fusions were identified. Idylla detected seven NTRK1 expression imbalances, in line with the NGS results (overall agreement 100%). Furthermore, Idylla detected the two NGS-identified ALK rearrangements as one specific ALK fusion and one ALK expression imbalance, whilst only two of the four RET fusions were discovered. However, Idylla detected several expression imbalances of ALK (n = 7) and RET (n = 1) that were found to be fusion negative with the NGS. Pan-TRK IHC showed clearly detectable, fusion partner-dependent staining patterns in the seven NTRK1 fusion cases. Overall agreement for pan-TRK antibody clone EPR17341 was 98% and for A7H6R 100% when compared to the NGS. Of the 62 CRCs, 43 were MLH1 promoter hypermethylated (MLH1ph) and 39 were RASwt. All fusion cases were both MLH1ph and RASwt. Our results show that kinase fusions (20/30, 67%) and most importantly targetable NTRK1 fusions (7/30, 23%) are frequent in CRCs with dMLH1/BRAFV600Ewt/MLH1ph/RASwt. NGS was the most comprehensive method in finding the fusions, of which a subset can be screened by Idylla or IHC, provided that the result is confirmed by NGS.
Collapse
Affiliation(s)
- Iiris Ukkola
- Department of Pathology, HUSLAB, HUS Diagnostic Center, Helsinki University Hospital and University of Helsinki, P.O. Box 400, 00029, HUS, Helsinki, Finland
- Applied Tumor Genomics Research Program, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Pirjo Nummela
- Applied Tumor Genomics Research Program, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Mia Kero
- Department of Pathology, HUSLAB, HUS Diagnostic Center, Helsinki University Hospital and University of Helsinki, P.O. Box 400, 00029, HUS, Helsinki, Finland
| | - Hanna Tammio
- Department of Genetics, HUSLAB, HUS Diagnostic Center, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Jenni Tuominen
- Department of Genomics, Laboratory of Molecular Haematology and Pathology, Turku University Central Hospital, Turku, Finland
| | - Veli Kairisto
- Department of Genomics, Laboratory of Molecular Haematology and Pathology, Turku University Central Hospital, Turku, Finland
| | - Markku Kallajoki
- Department of Pathology, University of Turku and Turku University Hospital, Turku, Finland
| | - Caj Haglund
- Department of Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Translational Cancer Medicine Research Program, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Päivi Peltomäki
- Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland
| | - Soili Kytölä
- Department of Genetics, HUSLAB, HUS Diagnostic Center, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Ari Ristimäki
- Department of Pathology, HUSLAB, HUS Diagnostic Center, Helsinki University Hospital and University of Helsinki, P.O. Box 400, 00029, HUS, Helsinki, Finland.
- Applied Tumor Genomics Research Program, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
| |
Collapse
|
|
4
|
Cherri S, Libertini M, Zaniboni A. New drugs for the treatment of metastatic colorectal cancer. World J Gastrointest Oncol 2021; 13:1551-1560. [PMID: 34853636 PMCID: PMC8603451 DOI: 10.4251/wjgo.v13.i11.1551] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 07/01/2021] [Accepted: 09/08/2021] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) represents one of the most frequent malignancies in terms of incidence and mortality, thus representing the third leading cause of cancer death worldwide. In the last decade, few drugs have enriched the treatment landscape of metastatic CRC and have significantly affected prognosis. Unlike other neoplasms, metastatic CRC patients who have exhausted treatment options often still maintain a good performance status. There are many challenges to increasing potential treatment options, notably a better understanding of disease biology and the mechanisms of resistance underlying cancer treatment failure. The development of new drugs for metastatic CRC certainly represents one of the most important challenges in medical oncology. This article discusses the main limitations in the development of new drugs and potential future scenarios. In particular, we addressed three questions: (1) The main limitations of targeted therapy in the treatment of metastatic CRC (mCRC); (2) New target armamentarium that could escape primary and secondary resistance and lead to more personalized mCRC therapy; and (3) Future directions.
Collapse
Affiliation(s)
- Sara Cherri
- Department of Oncology, Fondazione Poliambulanza, Brescia 25124, Italy
| | - Michela Libertini
- Department of Oncology, Fondazione Poliambulanza, Brescia 25124, Italy
| | - Alberto Zaniboni
- Department of Oncology, Fondazione Poliambulanza, Brescia 25124, Italy
| |
Collapse
|
|
5
|
He X, Jiao XD, Liu K, Qin BD, Wu Y, Ling Y, Liu J, Xu AQ, Song K, Zang YS. Clinical Responses to Crizotinib, Alectinib, and Lorlatinib in a Metastatic Colorectal Carcinoma Patient With ALK Gene Rearrangement: A Case Report. JCO Precis Oncol 2021; 5:PO.20.00534. [PMID: 34036227 PMCID: PMC8140796 DOI: 10.1200/po.20.00534] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 02/21/2021] [Accepted: 03/17/2021] [Indexed: 01/06/2023] Open
Affiliation(s)
- Xi He
- Department of Medical Oncology, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Xiao-Dong Jiao
- Department of Medical Oncology, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Ke Liu
- Department of Medical Oncology, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Bao-Dong Qin
- Department of Medical Oncology, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Ying Wu
- Department of Medical Oncology, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Yan Ling
- Department of Medical Oncology, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Jun Liu
- Department of Medical Oncology, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - A-Qiao Xu
- Shaoxing Central Hospital, Shaoxing, Zhejiang Province, China
| | - Kun Song
- Shaoxing People's Hospital, Shaoxing, Zhejiang Province, China
| | - Yuan-Sheng Zang
- Department of Medical Oncology, Changzheng Hospital, Naval Medical University, Shanghai, China
| |
Collapse
|
|
6
|
Goto K, Pissaloux D, Kauer F, Huriet V, Tirode F, de la Fouchardière A. GOPC-ROS1 mosaicism in agminated Spitz naevi: report of two cases. Virchows Arch 2021; 479:559-564. [PMID: 33733342 DOI: 10.1007/s00428-020-02992-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 12/06/2020] [Accepted: 12/08/2020] [Indexed: 02/02/2023]
Abstract
Spitz tumors are genetically associated with activating HRAS point mutations or fusions of either ALK, ROS1, NTRK1, NTRK3, RET, MET, MERTK, LCK, BRAF, MAP3K8, or MAP3K3. All these driver gene alterations are mutually exclusive. We report two cases of agminated Spitz naevi with a GOPC-ROS1 fusion. Both cases occurred on the lower limb of young adults. Since adolescence, pigmented or pink-colored papules have been periodically arising in a limited area of skin. In one case, an ill-defined hyperpigmented macule known since childhood was present in the background. Morphologically, at least five lesions were analyzed from each patient. In one case, all were predominantly junctional pigmented Spitz naevi, and in the other case, all were compound unpigmented Spitz naevi. No atypical features were present. RNA-sequencing revealed a GOPC-ROS1 gene translocation in both cases. Split signals of ROS1 gene in fluorescence in situ hybridization were observed not only in the nests of spitzoid melanocytes but also in the bland basal melanocytes surrounding the proliferations. These findings suggest the presence of a GOPC-ROS1 mosaicism in melanocytes with further emergence of agminated Spitz naevi potentially triggered by other genetic alterations. This expands the spectrum of genetic anomalies described in agminated Spitz naevi and our understanding of the mechanisms involved in their emergence.
Collapse
Affiliation(s)
- Keisuke Goto
- Department of Pathology, Tokyo Metropolitan Cancer and Infectious Disease Center Komagome Hospital, Tokyo, Japan.,Department of Pathology, Itabashi Central Clinical Laboratory, Tokyo, Japan.,Department of Diagnostic Pathology, Shizuoka Cancer Center Hospital, Nagaizumi, Japan.,Department of Diagnostic Pathology and Cytology, Osaka International Cancer Institute, Osaka, Japan.,Department of Dermatology, Hyogo Cancer Center, Akashi, Japan
| | - Daniel Pissaloux
- Department of Biopathology, Center Léon Bérard, 28, rue Laennec, 69008, Lyon, France.,Centre Léon Bérard, Cancer Research Center of Lyon, Equipe Labellisée Ligue contre le Cancer, Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Lyon, France
| | | | | | - Franck Tirode
- Department of Biopathology, Center Léon Bérard, 28, rue Laennec, 69008, Lyon, France.,Centre Léon Bérard, Cancer Research Center of Lyon, Equipe Labellisée Ligue contre le Cancer, Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Lyon, France
| | - Arnaud de la Fouchardière
- Department of Biopathology, Center Léon Bérard, 28, rue Laennec, 69008, Lyon, France. .,Centre Léon Bérard, Cancer Research Center of Lyon, Equipe Labellisée Ligue contre le Cancer, Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Lyon, France.
| |
Collapse
|
|
7
|
Hsiao SY, He HL, Weng TS, Lin CY, Chao CM, Huang WT, Tsao CJ. Colorectal Cancer with EML4-ALK Fusion Gene Response to Alectinib: A Case Report and Review of the Literature. Case Rep Oncol 2021; 14:232-238. [PMID: 33776709 PMCID: PMC7983623 DOI: 10.1159/000511069] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Accepted: 08/22/2020] [Indexed: 01/12/2023] Open
Abstract
Anti-epithelial growth factor receptor or anti-vascular endothelial growth factor agents combined with chemotherapy were the standard of treatment for metastatic colorectal cancer (CRC). However, increasing evidence of molecularly stratified treatment makes the complexity of treatment. Anaplastic lymphoma kinase (ALK) gene alternation is one of potential target for biomarker-guided therapy for CRC. We present a case of a 56-year-old man who suffered from advanced ascending colon cancer, harboring echinoderm microtubule associated protein-like 4 (EML4)-ALK fusion gene E21; A20 variant, a rare variant in EML4-ALK fusion gene in lung cancer. We also detected this fusion gene from different tissue types including circulating tumor DNA (ctDNA) and ascites fluid. The patient was offered alectinib, an ALK inhibitor, with partial response in lung, liver, and peritoneal metastasis for 8 months. Tumor heterogeneity, especially in gastrointestinal tract cancer, raise our interest in comprehensive genetic profiling in clinical practice. Convenience and reliability of next-generation sequencing, including using ctDNA, help physicians deal with clinical dilemma. ALK-positive CRC is rare. However, advanced CRC with ALK gene alteration responds to ALK inhibitor. It is reasonable to check ALK gene alteration in clinical practice for CRC.
Collapse
Affiliation(s)
- Sheng-Yen Hsiao
- Division of Hematology-Oncology, Department of Internal Medicine, Chi Mei Medical Center, Liouying, Tainan, Taiwan.,Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Hong-Lin He
- Department of Pathology, Chi Mei Medical Center, Tainan, Taiwan.,Department of Medical Laboratory Science and Biotechnology, Chung Hwa University of Medical Technology, Tainan, Taiwan
| | - Teng-Song Weng
- Department of Pharmacy, Chi Mei Medical Center, Liouying, Tainan, Taiwan
| | - Cheng-Yao Lin
- Division of Hematology-Oncology, Department of Internal Medicine, Chi Mei Medical Center, Liouying, Tainan, Taiwan
| | - Chien-Ming Chao
- Department of Intensive Care Medicine, Chi Mei Medical Center, Liouying, Tainan, Taiwan
| | - Wen-Tsung Huang
- Division of Hematology-Oncology, Department of Internal Medicine, Chi Mei Medical Center, Liouying, Tainan, Taiwan
| | - Chao-Jung Tsao
- Division of Hematology-Oncology, Department of Internal Medicine, Chi Mei Medical Center, Liouying, Tainan, Taiwan
| |
Collapse
|
|
8
|
Yonemaru J, Hashimoto T, Takayanagi D, Naka T, Yatabe Y, Kanemitsu Y, Shiraishi K, Sekine S. NTRK fusion-positive colorectal cancer in Japanese population. Pathol Int 2021; 71:355-359. [PMID: 33631044 DOI: 10.1111/pin.13082] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Accepted: 01/31/2021] [Indexed: 12/17/2022]
Abstract
ALK, ROS1 and NTRK fusions are involved in the tumorigenesis of various organs, including colorectal cancer. This study aims to clarify the prevalence of these fusions in colorectal cancer in the Japanese population. Immunohistochemical analysis of 1012 specimens of colorectal cancer revealed two NTRK-positive cases (0.2%) whereas no ALK- or ROS1-positive cases were identified. Reverse transcription polymerase chain reaction (RT-PCR) detected an LMNA-NTRK1 fusion in a case of adenosquamous carcinoma and a TPM3-NTRK1 fusion in a case of tubular adenocarcinoma. Both NTRK1 fusion-positive cases lacked activating mutations in KRAS and BRAF and were mismatch repair-deficient with loss of MLH1 and PMS2 expression and MLH1 promoter methylation. Our results show that receptor tyrosine kinase fusions are rare but present in colorectal cancers in Japanese patients, with a prevalence similar to that reported in other countries.
Collapse
Affiliation(s)
- Junpei Yonemaru
- Division of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, Japan
| | - Taiki Hashimoto
- Division of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, Japan
| | - Daisuke Takayanagi
- Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan
| | - Tomoaki Naka
- Division of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, Japan
| | - Yasushi Yatabe
- Division of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, Japan.,Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo, Japan
| | - Yukihide Kanemitsu
- Department of Colorectal Surgery, National Cancer Center Hospital, Tokyo, Japan
| | - Kouya Shiraishi
- Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan
| | - Shigeki Sekine
- Division of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, Japan.,Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo, Japan
| |
Collapse
|
|
9
|
Colorectal Adenocarcinomas Harboring ALK Fusion Genes: A Clinicopathologic and Molecular Genetic Study of 12 Cases and Review of the Literature. Am J Surg Pathol 2020; 44:1224-1234. [PMID: 32804454 DOI: 10.1097/pas.0000000000001512] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
This study determined the frequency and the clinicopathologic and genetic features of colorectal carcinomas driven by oncogenic fusions of the anaplastic lymphoma kinase gene (ALK). Of the 8150 screened tumors, 12 (0.15%) were immunohistochemically ALK-positive with D5F3 antibody. These cancers harbored CAD-ALK (n=1), DIAPH2-ALK (n=2), EML4-ALK (n=2), LOC101929227-ALK (n=1), SLMAP-ALK (n=1), SPTBN1-ALK (n=4), and STRN-ALK (n=1) fusions, as detected by an RNA-based next-generation sequencing assay. ALK fusion carcinomas were diagnosed mostly in older patients with a 9:3 female predominance (median age: 72 y). All tumors, except a rectal one, occurred in the right colon. Most tumors were stage T3 (n=7) or T4 (n=3). Local lymph node and distant metastases were seen at presentation in 9 and 2 patients. These tumors showed moderate (n=6) or poor (n=3) glandular differentiation, solid medullary growth pattern (n=2), and pure mucinous morphology (n=1). DNA mismatch repair-deficient phenotype was identified in 10 cases. Tumor-infiltrating lymphocytes were prominent in 9 carcinomas. In 4 carcinomas, tumor cells showed strong, focal (n=3), or diffuse programmed death-ligand 1 immunoreactivity. CDX2 expression and loss of CK20 and MUC2 expression were frequent. CK7 was expressed in 5 tumors. Four patients died of disease within 3 years, and 7 were alive with follow-up ranging from 1 to 8 years. No mutations in BRAF, RAS, and in genes encoding components of PI3K-AKT/MTOR pathway were identified. However, 1 tumor had a loss-of-function PTEN mutation. Aberration of p53 signaling, TP53 mutations, and/or nuclear accumulation of p53 protein was seen in 9 cases. ALK fusion colorectal carcinomas are a distinct and rare subtype of colorectal cancers displaying some features of mismatch repair-deficient tumors.
Collapse
|
|
10
|
Chan AWH, Pan Y, Tong JHM, Lung RWM, Kwan JSH, Chow C, Tin EKY, Chung LY, Li H, Wong SSY, Chau SL, Chan YY, Mak TWC, Ng SSM, To KF. Receptor tyrosine kinase fusions act as a significant alternative driver of the serrated pathway in colorectal cancer development. J Pathol 2020; 251:74-86. [PMID: 32162306 DOI: 10.1002/path.5418] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Revised: 02/18/2020] [Accepted: 03/02/2020] [Indexed: 02/06/2023]
Abstract
Serrated polyps are a clinically and molecularly heterogeneous group of lesions that can contribute to the development of colorectal cancers (CRCs). However, the molecular mechanism underlying the development of serrated lesions is still not well understood. Here, we combined multiple approaches to analyze the genetic alterations in 86 colorectal adenomas (including 35 sessile serrated lesions, 15 traditional adenomas, and 36 conventional adenomatous polyps). We also investigated the in vitro and in vivo oncogenic properties of a novel variant of the NCOA4-RET fusion gene. Molecular profiling revealed that sessile serrated lesions and traditional serrated adenomas have distinct clinicopathological and molecular features. Moreover, we identified receptor tyrosine kinase translocations exclusively in sessile serrated lesions (17%), and the observation was validated in a separate cohort of 34 sessile serrated lesions (15%). The kinase fusions as well as the BRAF and KRAS mutations were mutually exclusive to each other. Ectopic expression of a novel variant of the NCOA4-RET fusion gene promoted cell proliferation in vitro and in vivo, and the proliferation was significantly suppressed by RET kinase inhibitors. All of these underscored the importance of mitogen-activated protein kinase (MAPK) pathway activation in the serrated pathway of colorectal tumorigenesis. In addition, we demonstrated that the kinase fusion may occur early in the precursor lesion and subsequent loss of TP53 may drives the transformation to carcinoma during serrated tumorigenesis. In conclusion, we identified kinase fusions as a significant alternative driver of the serrated pathway in colorectal cancer development, and detecting their presence may serve as a biomarker for the diagnosis of sessile serrated lesions. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Collapse
Affiliation(s)
- Anthony W-H Chan
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, PR China
| | - Yi Pan
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, PR China.,Institute of Digestive Disease, State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, PR China.,Department of Pathology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China
| | - Joanna H-M Tong
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, PR China
| | - Raymond W-M Lung
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, PR China
| | - Johnny S-H Kwan
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, PR China
| | - Chit Chow
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, PR China
| | - Edith K-Y Tin
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, PR China
| | - Lau-Ying Chung
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, PR China
| | - Hui Li
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, PR China
| | - Shela S-Y Wong
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, PR China
| | - Shuk-Ling Chau
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, PR China
| | - Yuk Yu Chan
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, PR China
| | - Tony W-C Mak
- Division of Colorectal Surgery, Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, PR China
| | - Simon Siu-Man Ng
- Division of Colorectal Surgery, Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, PR China.,Institute of Digestive Disease, State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, PR China
| | - Ka-Fai To
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, PR China.,Institute of Digestive Disease, State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, PR China
| |
Collapse
|
|
11
|
Pagani F, Randon G, Guarini V, Raimondi A, Prisciandaro M, Lobefaro R, Di Bartolomeo M, Sozzi G, de Braud F, Gasparini P, Pietrantonio F. The Landscape of Actionable Gene Fusions in Colorectal Cancer. Int J Mol Sci 2019; 20:ijms20215319. [PMID: 31731495 PMCID: PMC6861915 DOI: 10.3390/ijms20215319] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Revised: 10/23/2019] [Accepted: 10/23/2019] [Indexed: 02/06/2023] Open
Abstract
The treatment scenario of metastatic colorectal cancer (mCRC) has been rapidly enriched with new chemotherapy combinations and biological agents that lead to a remarkable improvement in patients’ outcome. Kinase gene fusions account for less than 1% of mCRC overall but are enriched in patients with high microsatellite instability, RAS/BRAF wild-type colorectal cancer. mCRC patients harboring such alterations show a poor prognosis with standard treatments that could be reversed by adopting novel therapeutic strategies. Moving forward to a positive selection of mCRC patients suitable for targeted therapy in the era of personalized medicine, actionable gene fusions, although rare, represent a peculiar opportunity to disrupt a tumor alteration to achieve therapeutic goal. Here we summarize the current knowledge on potentially actionable gene fusions in colorectal cancer available from retrospective experiences and promising preliminary results of new basket trials.
Collapse
Affiliation(s)
- Filippo Pagani
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milano, Italy; (F.P.); (G.R.); (V.G.); (A.R.); (M.P.); (R.L.); (M.D.B.); (F.d.B.)
| | - Giovanni Randon
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milano, Italy; (F.P.); (G.R.); (V.G.); (A.R.); (M.P.); (R.L.); (M.D.B.); (F.d.B.)
| | - Vincenzo Guarini
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milano, Italy; (F.P.); (G.R.); (V.G.); (A.R.); (M.P.); (R.L.); (M.D.B.); (F.d.B.)
| | - Alessandra Raimondi
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milano, Italy; (F.P.); (G.R.); (V.G.); (A.R.); (M.P.); (R.L.); (M.D.B.); (F.d.B.)
| | - Michele Prisciandaro
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milano, Italy; (F.P.); (G.R.); (V.G.); (A.R.); (M.P.); (R.L.); (M.D.B.); (F.d.B.)
| | - Riccardo Lobefaro
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milano, Italy; (F.P.); (G.R.); (V.G.); (A.R.); (M.P.); (R.L.); (M.D.B.); (F.d.B.)
| | - Maria Di Bartolomeo
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milano, Italy; (F.P.); (G.R.); (V.G.); (A.R.); (M.P.); (R.L.); (M.D.B.); (F.d.B.)
| | - Gabriella Sozzi
- Unit of Molecular Cytogenetics, Fondazione IRCCS Istituto Nazionale Tumori, 20133 Milano, Italy; (G.S.); (P.G.)
| | - Filippo de Braud
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milano, Italy; (F.P.); (G.R.); (V.G.); (A.R.); (M.P.); (R.L.); (M.D.B.); (F.d.B.)
- Department of Oncology and Hemato-Oncology, University of Milan, 20122 Milan, Italy
| | - Patrizia Gasparini
- Unit of Molecular Cytogenetics, Fondazione IRCCS Istituto Nazionale Tumori, 20133 Milano, Italy; (G.S.); (P.G.)
| | - Filippo Pietrantonio
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milano, Italy; (F.P.); (G.R.); (V.G.); (A.R.); (M.P.); (R.L.); (M.D.B.); (F.d.B.)
- Department of Oncology and Hemato-Oncology, University of Milan, 20122 Milan, Italy
- Correspondence:
| |
Collapse
|
|
12
|
Wang J, Yi Y, Xiao Y, Dong L, Liang L, Teng L, Ying JM, Lu T, Liu Y, Guan Y, Pang J, Zhou L, Lu J, Zhang Z, Liu X, Liang X, Zeng X, Yi X, Zhou W, Xia X, Yang L, Zhang J, Kopetz S, Futreal PA, Wu H, Liang Z. Prevalence of recurrent oncogenic fusion in mismatch repair-deficient colorectal carcinoma with hypermethylated MLH1 and wild-type BRAF and KRAS. Mod Pathol 2019; 32:1053-1064. [PMID: 30723297 DOI: 10.1038/s41379-019-0212-1] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2018] [Revised: 12/31/2018] [Accepted: 12/31/2018] [Indexed: 01/04/2023]
Abstract
Oncogenic fusions are rare in colorectal carcinomas, but may be important for prognosis and therapy. An effective strategy for screening targetable oncogenic fusions in colorectal carcinomas is needed. Here, we investigate molecular genetic alterations in colorectal carcinomas based on their DNA mismatch repair status, and to effectively screen for targetable oncogenic fusions in colorectal carcinomas. In this retrospective study, the initial cohort included 125 consecutive mismatch repair-deficient and 238 randomly selected mismatch repair-proficient colorectal carcinomas diagnosed between July 2015 and December 2017 at Peking Union Medical College Hospital. Targeted sequencing was performed. MLH1 promoter hypermethylation analysis was further employed for subgrouping dMMR colorectal carcinomas. Clinicopathological characteristics, molecular features, and survival outcome of colorectal carcinomas harboring oncogenic fusions were assessed. A multicenter cohort comprised of 227 colorectal carcinomas with dual loss of MLH1/PMS2 was used to validate the efficacy of the proposed screening strategy for oncogenic fusions. Of the 363 patients in the initial cohort, 11(3.0%) harbored oncogenic fusions and were all mismatch repair-deficient colorectal carcinomas with hypermethylated MLH1 and wild-type BRAF and KRAS, comprising 55% (11/20) of this subgroup. These patients with oncogenic fusions showed poorer 3-year cancer-specific survival compared with other Stage III/IV mismatch repair-deficient colorectal carcinoma patients (40% vs. 97%), and significantly higher CD274(PD-L1) expression in tumor cells compared with other dMMR colorectal carcinoma patients (46% vs. 6.1%, P < 0.001). An easy-to-perform and cost-efficient strategy for screening targetable fusions was proposed based on the current molecular testing algorithms for colorectal carcinomas, and validated in an independent multicenter cohort. In conclusion, oncogenic fusions were highly enriched and frequently detected in mismatch repair-deficient colorectal carcinomas with MLH1 hypermethylation and wild-type BRAF and KRAS, and were associated with poor prognosis and high tumor CD274(PD-L1) expression.
Collapse
Affiliation(s)
- Jing Wang
- Molecular Pathology Research Center, Department of Pathology, Peking Union Medical College Hospital, and Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yuting Yi
- Geneplus-Beijing Institute, Beijing, China
| | - Yi Xiao
- Department of Surgery, Peking Union Medical College Hospital, and Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Lin Dong
- Departments of Pathology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Li Liang
- Department of Pathology, Nanfang Hospital, Guangzhou, Guangdong, China
| | - Lianghong Teng
- Department of Pathology, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Jian Ming Ying
- Departments of Pathology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Tao Lu
- Molecular Pathology Research Center, Department of Pathology, Peking Union Medical College Hospital, and Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yuanyuan Liu
- Molecular Pathology Research Center, Department of Pathology, Peking Union Medical College Hospital, and Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | | | - Junyi Pang
- Molecular Pathology Research Center, Department of Pathology, Peking Union Medical College Hospital, and Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Lianrui Zhou
- Molecular Pathology Research Center, Department of Pathology, Peking Union Medical College Hospital, and Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Junliang Lu
- Molecular Pathology Research Center, Department of Pathology, Peking Union Medical College Hospital, and Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zhiwen Zhang
- Molecular Pathology Research Center, Department of Pathology, Peking Union Medical College Hospital, and Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiaoding Liu
- Molecular Pathology Research Center, Department of Pathology, Peking Union Medical College Hospital, and Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiaolong Liang
- Molecular Pathology Research Center, Department of Pathology, Peking Union Medical College Hospital, and Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xuan Zeng
- Molecular Pathology Research Center, Department of Pathology, Peking Union Medical College Hospital, and Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xin Yi
- Geneplus-Beijing Institute, Beijing, China
| | - Weixun Zhou
- Molecular Pathology Research Center, Department of Pathology, Peking Union Medical College Hospital, and Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xuefeng Xia
- Houston Methodist Research Institute, Houston, TX, USA
| | - Ling Yang
- Geneplus-Beijing Institute, Beijing, China
| | - Jianjun Zhang
- Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.,Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Scott Kopetz
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - P Andrew Futreal
- Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Huanwen Wu
- Molecular Pathology Research Center, Department of Pathology, Peking Union Medical College Hospital, and Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| | - Zhiyong Liang
- Molecular Pathology Research Center, Department of Pathology, Peking Union Medical College Hospital, and Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| |
Collapse
|
|
13
|
Tessier-Cloutier B, Cai E, Schaeffer DF. Off-label use of common predictive biomarkers in gastrointestinal malignancies: a critical appraisal. Diagn Pathol 2019; 14:62. [PMID: 31221175 PMCID: PMC6587260 DOI: 10.1186/s13000-019-0843-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Accepted: 06/11/2019] [Indexed: 12/13/2022] Open
Abstract
The use of immunohistochemistry (IHC) as a companion diagnostic is an increasingly important part of the case workup by pathologists and is often central to clinical decision making. New predictive molecular markers are constantly sought for to improve treatment stratification parallel to drug development. Unfortunately, official biomarker guidelines lag behind, and pathologists are often left hesitating when medical oncologists request off-labelled biomarker testing. We performed a literature review of five commonly requested off-label IHC predictive biomarkers in gastrointestinal tract (GIT) malignancies: HER2, mismatch repair (MMR), PD-L1, BRAF V600E and ROS1. We found that HER2 amplification is rare and poorly associated to IHC overexpression in extracolonic and extragastric GIT cancers; however in KRAS wild type colorectal cancers, which fail conventional treatment, HER2 IHC may be useful and should be considered. For MMR testing, more evidence is needed to recommend reflex testing in GIT cancers for treatment purposes. MMR testing should not be discouraged in patients considered for second line checkpoint inhibitor therapy. With the exception of gastric tumors, PD-L1 IHC is a weak predictor of checkpoint inhibitor response in the GIT and should be replaced by MMR in this context. BRAF inhibitors showed activity in BRAF V600E mutated cholangiocarcinomas and pancreatic carcinomas in non-first line settings. ROS1 translocation is extremely rare and poorly correlated to ROS1 IHC expression in the GIT; currently there is no role for ROS1 IHC testing in GIT cancers. Overall, the predictive biomarker literature has grown exponentially, and official guidelines need to be updated more regularly to support pathologists’ testing decisions.
Collapse
Affiliation(s)
- Basile Tessier-Cloutier
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.,Department of Pathology and Laboratory Medicine, Vancouver General Hospital, 910 West 10th Ave, Vancouver, BC, Canada
| | - Ellen Cai
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.,Department of Pathology and Laboratory Medicine, Vancouver General Hospital, 910 West 10th Ave, Vancouver, BC, Canada
| | - David F Schaeffer
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada. .,Department of Pathology and Laboratory Medicine, Vancouver General Hospital, 910 West 10th Ave, Vancouver, BC, Canada.
| |
Collapse
|
|
14
|
Jiang W, Ji M. Receptor tyrosine kinases in PI3K signaling: The therapeutic targets in cancer. Semin Cancer Biol 2019; 59:3-22. [PMID: 30943434 DOI: 10.1016/j.semcancer.2019.03.006] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2018] [Revised: 03/09/2019] [Accepted: 03/28/2019] [Indexed: 12/17/2022]
Abstract
The phosphoinositide 3-kinase (PI3K) pathway, one of the most commonly activated signaling pathways in human cancers, plays a crucial role in the regulation of cell proliferation, differentiation, and survival. This pathway is usually activated by receptor tyrosine kinases (RTKs), whose constitutive and aberrant activation is via gain-of-function mutations, chromosomal rearrangement, gene amplification and autocrine. Blockage of PI3K pathway by targeted therapy on RTKs with tyrosine kinases inhibitors (TKIs) and monoclonal antibodies (mAbs) has achieved great progress in past decades; however, there still remain big challenges during their clinical application. In this review, we provide an overview about the most frequently encountered alterations in RTKs and focus on current therapeutic agents developed to counteract their aberrant functions, accompanied with discussions of two major challenges to the RTKs-targeted therapy in cancer - resistance and toxicity.
Collapse
Affiliation(s)
- Wei Jiang
- Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China; Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China
| | - Meiju Ji
- Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China; Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China.
| |
Collapse
|
|
15
|
Pietrantonio F, Di Nicolantonio F, Schrock AB, Lee J, Tejpar S, Sartore-Bianchi A, Hechtman JF, Christiansen J, Novara L, Tebbutt N, Fucà G, Antoniotti C, Kim ST, Murphy D, Berenato R, Morano F, Sun J, Min B, Stephens PJ, Chen M, Lazzari L, Miller VA, Shoemaker R, Amatu A, Milione M, Ross JS, Siena S, Bardelli A, Ali SM, Falcone A, de Braud F, Cremolini C. ALK, ROS1, and NTRK Rearrangements in Metastatic Colorectal Cancer. J Natl Cancer Inst 2019; 109:3860155. [PMID: 29370427 DOI: 10.1093/jnci/djx089] [Citation(s) in RCA: 177] [Impact Index Per Article: 29.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Accepted: 04/11/2017] [Indexed: 12/12/2022] Open
Abstract
Background ALK, ROS1, and NTRK fusions occur in 0.2% to 2.4% of colorectal cancers. Pioneer cases of metastatic colorectal cancer (mCRC) patients bearing rearrangements who benefited from anti-ALK, ROS, and TrkA-B-C therapies have been reported previously. Here we aimed at characterizing the clinical and molecular landscape of ALK, ROS1, and NTRK rearranged mCRC. Methods Clinical features and molecular characteristics of 27 mCRC patients bearing ALK, ROS1, and NTRK rearranged tumors were compared with those of a cohort of 319 patients not bearing rearrangements by means of Fisher's exact, χ2 test, or Mann-Whitney test as appropriate. Overall survival curves were estimated with the Kaplan-Meier method and compared using the log-rank test. A Cox proportional hazard model was adopted in the multivariable analysis. Deep molecular and immunophenotypic characterizations of rearranged cases, including those described in The Cancer Genome Atlas database, were performed. All statistical tests were two-sided. Results Closely recalling the "BRAF history," ALK, ROS1, and NTRK rearrangements more frequently occurred in elderly patients (P = .02) with right-sided tumors (P < .001) and node-spreading (P = .03), RAS wild-type (P < .001), and MSI-high (P < .001) cancers. All patients bearing ALK, ROS1, and NTRK fusions had shorter overall survival (15.6 months, 95% confidence interval [CI] = 0.0 to 20.4 months) than negative patients (33.7 months, 95% CI = 28.3 to 42.1 months), both in the univariate (hazard ratio [HR] = 2.17, 95% CI = 1.03 to 4.57, P < .001) and multivariable models (HR = 2.33, 95% CI = 1.10 to 4.95, P = .02). All four evaluable patients with rearrangements showed primary resistance to anti-epidermal growth factor receptor agents. Frequent association with potentially targetable RNF43 mutations was observed in MSI-high rearranged tumors. Conclusions ALK, ROS1, and NTRK rearrangements define a new rare subtype of mCRC with extremely poor prognosis. Primary tumor site, MSI-high, and RAS and BRAF wild-type status may help to identify patients bearing these alterations. While sensitivity to available treatments is limited, targeted strategies inhibiting ALK, ROS, and TrkA-B-C provided encouraging results.
Collapse
Affiliation(s)
- Filippo Pietrantonio
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Federica Di Nicolantonio
- Department of Oncology, University of Torino, Candiolo, Italy.,Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Italy
| | | | - Jeeyun Lee
- Samsung Medical Center, Sungkyunkwan University School of Medicine, Kangnamgu, Seoul, Korea
| | - Sabine Tejpar
- Molecular Digestive Oncology Unit, University Hospital Gasthuisberg, Leuven, Belgium
| | | | | | | | - Luca Novara
- Department of Oncology, University of Torino, Candiolo, Italy
| | | | - Giovanni Fucà
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Carlotta Antoniotti
- Azienda Ospedaliero, Universitaria Pisana, Pisa, Italy.,University of Pisa, Pisa, Italy
| | - Seung Tae Kim
- Samsung Medical Center, Sungkyunkwan University School of Medicine, Kangnamgu, Seoul, Korea
| | | | - Rosa Berenato
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Federica Morano
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - James Sun
- Foundation Medicine, Inc., Cambridge, MA
| | | | | | | | - Luca Lazzari
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Vincent A Miller
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Robert Shoemaker
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Alessio Amatu
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Massimo Milione
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Jeffrey S Ross
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Salvatore Siena
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Alberto Bardelli
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Siraj M Ali
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Alfredo Falcone
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Filippo de Braud
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Chiara Cremolini
- Azienda Ospedaliero, Universitaria Pisana, Pisa, Italy.,University of Pisa, Pisa, Italy
| |
Collapse
|
|
16
|
Roussille P, Tachon G, Villalva C, Milin S, Frouin E, Godet J, Berger A, Emambux S, Petropoulos C, Wager M, Karayan-Tapon L, Tougeron D. Pathological and Molecular Characteristics of Colorectal Cancer with Brain Metastases. Cancers (Basel) 2018; 10:504. [PMID: 30544743 PMCID: PMC6316286 DOI: 10.3390/cancers10120504] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2018] [Revised: 11/30/2018] [Accepted: 12/05/2018] [Indexed: 02/01/2023] Open
Abstract
Background: Colorectal cancers (CRC) with brain metastases (BM) are scarcely described. The main objective of this study was to determine the molecular profile of CRC with BM. Methods: We included 82 CRC patients with BM. KRAS, NRAS, BRAF and mismatch repair (MMR) status were investigated on primary tumors (n = 82) and BM (n = 38). ALK, ROS1, cMET, HER-2, PD-1, PD-L1, CD3 and CD8 status were evaluated by immunohistochemistry, and when recommended, by fluorescence in situ hybridization. Results: In primary tumors, KRAS, NRAS and BRAF mutations were observed in 56%, 6%, and 6% of cases, respectively. No ROS1, ALK and cMET rearrangement was detected. Only one tumor presented HER-2 amplification. Molecular profiles were mostly concordant between BM and paired primary tumors, except for 9% of discordances for RAS mutation. CD3, CD8, PD-1 and PD-L1 expressions presented some discordance between primary tumors and BM. In multivariate analysis, multiple BM, lung metastases and PD-L1+ tumor were predictive of poor overall survival. Conclusions: CRCs with BM are associated with high frequency of RAS mutations and significant discordance for RAS mutational status between BM and paired primary tumors. Multiple BM, lung metastases and PD-L1+ have been identified as prognostic factors and can guide therapeutic decisions for CRC patients with BM.
Collapse
Affiliation(s)
- Pauline Roussille
- Department of Radiation Oncology, University Hospital of Poitiers, 86021 Poitiers, France.
- INSERM 1084, Experimental and Clinical Neurosciences Laboratory, University of Poitiers, 86073 Poitiers, France.
- Faculty of Medicine, University of Poitiers, 86021 Poitiers, France.
| | - Gaelle Tachon
- INSERM 1084, Experimental and Clinical Neurosciences Laboratory, University of Poitiers, 86073 Poitiers, France.
- Faculty of Medicine, University of Poitiers, 86021 Poitiers, France.
- Cancer Biology Department, University Hospital of Poitiers, 86021 Poitiers, France.
| | - Claire Villalva
- Cancer Biology Department, University Hospital of Poitiers, 86021 Poitiers, France.
| | - Serge Milin
- Pathology Department, University Hospital of Poitiers, 86021 Poitiers, France.
| | - Eric Frouin
- Faculty of Medicine, University of Poitiers, 86021 Poitiers, France.
- Pathology Department, University Hospital of Poitiers, 86021 Poitiers, France.
| | - Julie Godet
- Pathology Department, University Hospital of Poitiers, 86021 Poitiers, France.
| | - Antoine Berger
- Department of Radiation Oncology, University Hospital of Poitiers, 86021 Poitiers, France.
| | - Sheik Emambux
- INSERM 1084, Experimental and Clinical Neurosciences Laboratory, University of Poitiers, 86073 Poitiers, France.
- Faculty of Medicine, University of Poitiers, 86021 Poitiers, France.
- Cancer Biology Department, University Hospital of Poitiers, 86021 Poitiers, France.
- Medical Oncology Department, University Hospital of Poitiers, 86021 Poitiers, France.
| | - Christos Petropoulos
- INSERM 1084, Experimental and Clinical Neurosciences Laboratory, University of Poitiers, 86073 Poitiers, France.
- Faculty of Medicine, University of Poitiers, 86021 Poitiers, France.
- Cancer Biology Department, University Hospital of Poitiers, 86021 Poitiers, France.
| | - Michel Wager
- INSERM 1084, Experimental and Clinical Neurosciences Laboratory, University of Poitiers, 86073 Poitiers, France.
- Faculty of Medicine, University of Poitiers, 86021 Poitiers, France.
- Department of Neurosurgery, University Hospital of Poitiers, 86021 Poitiers, France.
| | - Lucie Karayan-Tapon
- INSERM 1084, Experimental and Clinical Neurosciences Laboratory, University of Poitiers, 86073 Poitiers, France.
- Faculty of Medicine, University of Poitiers, 86021 Poitiers, France.
- Cancer Biology Department, University Hospital of Poitiers, 86021 Poitiers, France.
| | - David Tougeron
- Faculty of Medicine, University of Poitiers, 86021 Poitiers, France.
- Medical Oncology Department, University Hospital of Poitiers, 86021 Poitiers, France.
- Department of Gastroenterology, University Hospital of Poitiers, 86021 Poitiers, France.
| |
Collapse
|
|
17
|
Antoniotti C, Ongaro E, Falcone A, Cremolini C. The Winding Roadmap of Biomarkers toward Clinic: Lessons from Predictors of Resistance to Anti-EGFRs in Metastatic Colorectal Cancer. Int J Mol Sci 2018; 19:E2298. [PMID: 30081606 PMCID: PMC6121538 DOI: 10.3390/ijms19082298] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2018] [Revised: 07/31/2018] [Accepted: 08/01/2018] [Indexed: 01/06/2023] Open
Abstract
In the evolving molecular landscape of metastatic colorectal cancer, optimizing available tools to select patients to receive anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibodies is a modern challenge of colorectal oncologists. Several molecular biomarkers have been investigated in recent years as potential predictors of resistance to anti-EGFR agents in preclinical and clinical retrospective series. Nevertheless, none of them have been implemented in clinical practice due to the lack of a formal prospective demonstration. Here, we propose a literature review of molecular alterations associated with resistance to anti-EGFRs, underlining the reasons why their roadmap from laboratories to clinics was prematurely halted.
Collapse
Affiliation(s)
- Carlotta Antoniotti
- Department of Oncology, University Hospital of Pisa, 56126 Pisa, Italy.
- Department of Translational Research and New Technologies in Medicine, University of Pisa, 56126 Pisa, Italy.
| | - Elena Ongaro
- Department of Oncology, University Hospital of Pisa, 56126 Pisa, Italy.
- Department of Translational Research and New Technologies in Medicine, University of Pisa, 56126 Pisa, Italy.
- Department of Oncology, Azienda Sanitaria Universitaria Integrata S. Maria della Misericordia, 33100 Udine, Italy.
| | - Alfredo Falcone
- Department of Oncology, University Hospital of Pisa, 56126 Pisa, Italy.
- Department of Translational Research and New Technologies in Medicine, University of Pisa, 56126 Pisa, Italy.
| | - Chiara Cremolini
- Department of Oncology, University Hospital of Pisa, 56126 Pisa, Italy.
- Department of Translational Research and New Technologies in Medicine, University of Pisa, 56126 Pisa, Italy.
| |
Collapse
|
|
18
|
NRASQ61R Mutation-specific Immunohistochemistry is Highly Specific for Either NRAS Q61R or KRAS Q61R Mutation in Colorectal Carcinoma. Appl Immunohistochem Mol Morphol 2017; 25:475-480. [DOI: 10.1097/pai.0000000000000333] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
|
|
19
|
Lai AZ, Schrock AB, Erlich RL, Ross JS, Miller VA, Yakirevich E, Ali SM, Braiteh F. Detection of an ALK Fusion in Colorectal Carcinoma by Hybrid Capture-Based Assay of Circulating Tumor DNA. Oncologist 2017; 22:774-779. [PMID: 28507204 PMCID: PMC5507649 DOI: 10.1634/theoncologist.2016-0376] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Accepted: 02/17/2017] [Indexed: 01/12/2023] Open
Abstract
ALK rearrangements have been observed in 0.05%-2.5% of patients with colorectal cancers (CRCs) and are predicted to be oncogenic drivers largely mutually exclusive of KRAS, NRAS, or BRAF alterations. Here we present the case of a patient with metastatic CRC who was treatment naïve at the time of molecular testing. Initial ALK immunohistochemistry (IHC) staining was negative, but parallel genomic profiling of both circulating tumor DNA (ctDNA) and tissue using similar hybrid capture-based assays each identified an identical STRN-ALK fusion. Subsequent ALK IHC staining of the same specimens was positive, suggesting that the initial result was a false negative. This report is the first instance of an ALK fusion in CRC detected using a ctDNA assay. KEY POINTS Current guidelines for colorectal cancer (CRC) only recommend genomic assessment of KRAS, NRAS, BRAF, and microsatellite instability (MSI) status.ALK rearrangements are rare in CRC, but patients with activating ALK fusions have responded to targeted therapiesALK rearrangements can be detected by genomic profiling of ctDNA from blood or tissue, and this methodology may be informative in cases where immunohistochemistry (IHC) or other standard testing is negative.
Collapse
Affiliation(s)
- Andrea Z Lai
- Foundation Medicine, Inc., Cambridge, Massachusetts, USA
| | | | | | - Jeffrey S Ross
- Foundation Medicine, Inc., Cambridge, Massachusetts, USA
| | | | - Evgeny Yakirevich
- Department of Pathology, Rhode Island Hospital, Alpert Medical School, Brown University, Providence, Rhode Island, USA
| | - Siraj M Ali
- Foundation Medicine, Inc., Cambridge, Massachusetts, USA
| | - Fadi Braiteh
- Comprehensive Cancer Centers of Nevada, Las Vegas, Nevada, USA
- University of Nevada School of Medicine, Reno, Nevada, USA
| |
Collapse
|
|
20
|
How the lab is changing our view of colorectal cancer. TUMORI JOURNAL 2016; 102:541-547. [PMID: 27647226 DOI: 10.5301/tj.5000551] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/25/2016] [Indexed: 12/19/2022]
Abstract
In metastatic colorectal cancer, the optimization of upfront treatment and the continuum of care based on patients' exposure to multiple treatment lines have reached a plateau of efficacy. Therefore, a paradigm shift is ongoing towards precision medicine and personalized treatments based on the specific molecular features of the disease. In this perspective, the improved knowledge of disease biology coming from the lab has prompted a rapid translation from bench to bedside of newer targeted strategies. Here, we focus on the most promising biomarkers already included or close to adoption in daily clinical practice. In particular, evidence about the potential roles of BRAF mutation, HER2 amplification, MGMT methylation, microsatellite instability, and ALK, ROS and NTRK1-3 rearrangements as positive predictors of benefit from biological agents is reviewed and discussed.
Collapse
|
|
21
|
Lee J, Kim HC, Hong JY, Wang K, Kim SY, Jang J, Kim ST, Park JO, Lim HY, Kang WK, Park YS, Lee J, Lee WY, Park YA, Huh JW, Yun SH, Do IG, Kim SH, Balasubramanian S, Stephens PJ, Ross JS, Li GG, Hornby Z, Ali SM, Miller VA, Kim KM, Ou SHI. Detection of novel and potentially actionable anaplastic lymphoma kinase (ALK) rearrangement in colorectal adenocarcinoma by immunohistochemistry screening. Oncotarget 2016; 6:24320-32. [PMID: 26172300 PMCID: PMC4695188 DOI: 10.18632/oncotarget.4462] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2015] [Accepted: 06/19/2015] [Indexed: 11/29/2022] Open
Abstract
Purpose Anaplastic lymphoma kinase (ALK) rearrangement has been detected in colorectal carcinoma (CRC) using advanced molecular diagnostics tests including exon scanning, fluorescence in situ hybridization (FISH), and next generation sequencing (NGS). We investigated if immunohistochemistry (IHC) can be used to detect ALK rearrangement in gastrointestinal malignancies. Experimental designs Tissue microarrays (TMAs) from consecutive gastric carcinoma (GC) and CRC patients who underwent surgical resection at Samsung Medical Center, Seoul, Korea were screened by IHC using ALK monoclonal antibody 5A4. IHC positive cases were confirmed by FISH, nCounter assays, and NGS-based comprehensive genomic profiling (CGP). ALK IHC was further applied to CRC patients enrolled in a pathway-directed therapeutic trial. Results Four hundred thirty-two GC and 172 CRC cases were screened by IHC. No GC sample was ALK IHC positive. One CRC (0.6%) was ALK IHC positive (3+) that was confirmed by ALK FISH and a novel CAD-ALK (C35; A20) fusion variant that resulted from a paracentric inversion event inv(2)(p22–21p23) was identified by CGP. One out of 50 CRC patients enrolled in a pathway-directed therapeutic trial was ALK IHC positive (3+) confirmed by ALK FISH and found to harbor the EML4-ALK (E21, A20) fusion variant by CGP. Growth of a tumor cell line derived from this EML4-ALK CRC patient was inhibited by ALK inhibitors crizotinib and entrectinib. Conclusions ALK IHC is a viable screening strategy for identifying ALK rearrangement in CRC. ALK rearrangement is a potential actionable driver mutation in CRC based on survival inhibition of patient tumor-derived cell line by potent ALK inhibitors.
Collapse
Affiliation(s)
- Jeeyun Lee
- Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Hee Cheol Kim
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Jung Yong Hong
- Department of Internal Medicine, Chung-Ang University College of Medicine, Dongjak-Gu, Seoul, Republic of Korea
| | - Kai Wang
- Foundation Medicine Inc, Cambridge, Massachusetts, USA
| | - Sun Young Kim
- Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Jiryeon Jang
- Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Seung Tae Kim
- Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Joon Oh Park
- Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Ho Yeong Lim
- Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Won Ki Kang
- Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Young Suk Park
- Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Jiyun Lee
- Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Woo Yong Lee
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Yoon Ah Park
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Jung Wook Huh
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Seong Hyeon Yun
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - In-Gu Do
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Seok Hyung Kim
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | | | | | - Jeffrey S Ross
- Foundation Medicine Inc, Cambridge, Massachusetts, USA.,Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, New York, USA
| | | | | | - Siraj M Ali
- Foundation Medicine Inc, Cambridge, Massachusetts, USA
| | | | - Kyoung-Mee Kim
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.,Innovative Cancer Medicine Institute, Samsung Medical Center, Seoul, Korea
| | - Sai-Hong Ignatius Ou
- Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Orange, California, USA
| |
Collapse
|
|
22
|
Ahadi M, Andrici J, Sioson L, Sheen A, Clarkson A, Gill AJ. Loss of Hes1 expression is associated with poor prognosis in colorectal adenocarcinoma. Hum Pathol 2016; 57:91-97. [PMID: 27476040 DOI: 10.1016/j.humpath.2016.07.010] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2016] [Revised: 07/01/2016] [Accepted: 07/06/2016] [Indexed: 01/08/2023]
Abstract
Alterations in the Notch signaling pathway play a role in colorectal cancer (CRC). Hes1, a Notch-induced transcription factor, has recently been reported to show decreased expression by immunohistochemistry in sessile serrated adenomas. Variable staining patterns have been reported in tubular adenomas, and existing data on Hes1 expression in CRC are limited and inconsistent. We therefore sought to investigate the expression of Hes1 by immunohistochemistry in a large and well-characterized cohort of CRC patients to determine clinicopathological associations and prognostic significance. Immunohistochemistry for Hes1 was performed on 2775 consecutive CRCs in tissue microarray format. Hes1 expression was classified into 3 categories: absent, 1302 cases (46.9%); cytoplasmic staining only with loss of nuclear staining, 1002 cases (36.1%); and nuclear with or without cytoplasmic staining, 471 cases (17%). In univariate analysis, loss of nuclear expression of HES1 was significantly associated with older age, female sex, right-sided location, mucinous or medullary histology, higher histological grade, microsatellite instability, BRAFV600E mutation, and larger tumor size. Strong and statistically significant associations with female sex, right-sided location, BRAFV600E mutation, microsatellite instability, and larger size remained in multivariate analysis. Patients with loss of nuclear expression of Hes1 had a significantly worse all-cause 5-year survival in both univariate (P = .002) and multivariate (P = .009) analysis. We conclude that loss of nuclear expression of Hes1 occurs in 83% of CRCs when studied in tissue microarray format and is associated with female sex, right-sided location, BRAFV600E mutation, microsatellite instability, larger tumor size, and significantly worse survival.
Collapse
Affiliation(s)
- Mahsa Ahadi
- Department of Anatomical Pathology, Royal North Shore Hospital, St Leonards, NSW, Australia, 2065; Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research, St Leonards, NSW, Australia, 2065
| | - Juliana Andrici
- Department of Anatomical Pathology, Royal North Shore Hospital, St Leonards, NSW, Australia, 2065; Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research, St Leonards, NSW, Australia, 2065; Sydney Medical School, University of Sydney, NSW, Australia, 2006
| | - Loretta Sioson
- Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research, St Leonards, NSW, Australia, 2065
| | - Amy Sheen
- Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research, St Leonards, NSW, Australia, 2065
| | - Adele Clarkson
- Department of Anatomical Pathology, Royal North Shore Hospital, St Leonards, NSW, Australia, 2065; Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research, St Leonards, NSW, Australia, 2065; Sydney Medical School, University of Sydney, NSW, Australia, 2006
| | - Anthony J Gill
- Department of Anatomical Pathology, Royal North Shore Hospital, St Leonards, NSW, Australia, 2065; Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research, St Leonards, NSW, Australia, 2065; Sydney Medical School, University of Sydney, NSW, Australia, 2006.
| |
Collapse
|
|
23
|
Yang Y, Wu N, Shen J, Teixido C, Sun X, Lin Z, Qian X, Zou Z, Guan W, Yu L, Rosell R, Liu B, Wei J. MET overexpression and amplification define a distinct molecular subgroup for targeted therapies in gastric cancer. Gastric Cancer 2016; 19:778-88. [PMID: 26404902 DOI: 10.1007/s10120-015-0545-5] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2015] [Accepted: 09/07/2015] [Indexed: 02/07/2023]
Abstract
BACKGROUND Currently, only trastuzumab, ramucirumab, and apatinib effectively treat gastric cancer. Thus, additional novel targets are required for this disease. METHODS We investigated the immunohistochemical and fluorescence in situ hybridization expression of MET, ROS1, and ALK in four gastric cell lines and a cohort of 98 gastric cancer patients. Crizotinib response was studied in vitro and in vivo. RESULTS Crizotinib potently inhibited in vitro cell growth in only one cell line, which also showed MET amplification. A positive correlation between crizotinib sensitivity and MET overexpression was observed (P = 0.045) in the histoculture drug response assay. Meanwhile, patient-derived tumor xenograft mouse models transplanted with tissues with higher MET protein expression displayed a highly selective sensitivity to crizotinib. In the 98 patients, MET overexpression was found in 42 (42.9 %) and MET was amplified in 4 (4.1 %). ROS1 and ALK overexpression were found in 25 (25.5 %) and 0 patients, respectively. However, none of the patients screened harbored ALK or ROS1 rearrangements. No significant association was found between overall survival and MET or ROS1 status. We also observed a stage IV gastric cancer patient with MET amplification who experienced tumor shrinkage and clinical benefit after 3 weeks of crizotinib as fourth-line treatment. CONCLUSIONS Crizotinib may induce clinically relevant anticancer effects in MET-overexpressed or MET-amplified gastric cancer patients.
Collapse
Affiliation(s)
- Yang Yang
- The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University, 321 Zhongshan Road, Nanjing, 210008, China
| | - Nandie Wu
- The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University, 321 Zhongshan Road, Nanjing, 210008, China
| | - Jie Shen
- The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University, 321 Zhongshan Road, Nanjing, 210008, China
| | - Cristina Teixido
- Pangaea Biotech, USP Dexeus University Institute, Barcelona, Spain
| | - Xia Sun
- The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University, 321 Zhongshan Road, Nanjing, 210008, China
| | - Zihan Lin
- The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University, 321 Zhongshan Road, Nanjing, 210008, China
| | - Xiaoping Qian
- The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University, 321 Zhongshan Road, Nanjing, 210008, China
| | - Zhengyun Zou
- The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University, 321 Zhongshan Road, Nanjing, 210008, China
| | - Wenxian Guan
- Department of General Surgery, Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
| | - Lixia Yu
- The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University, 321 Zhongshan Road, Nanjing, 210008, China
| | - Rafael Rosell
- Pangaea Biotech, USP Dexeus University Institute, Barcelona, Spain
- Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Medical Oncology Service, Badalona, Spain
| | - Baorui Liu
- The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University, 321 Zhongshan Road, Nanjing, 210008, China
| | - Jia Wei
- The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University, 321 Zhongshan Road, Nanjing, 210008, China.
| |
Collapse
|
|
24
|
Andrici J, Parkhill TR, Jung J, Wardell KL, Verdonk B, Singh A, Sioson L, Clarkson A, Watson N, Sheen A, Farzin M, Toon CW, Gill AJ. Loss of expression of BAP1 is very rare in non-small cell lung carcinoma. Pathology 2016; 48:336-40. [DOI: 10.1016/j.pathol.2016.03.005] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2016] [Revised: 03/11/2016] [Accepted: 03/14/2016] [Indexed: 12/30/2022]
|
|
25
|
Wang J, Andrici J, Sioson L, Clarkson A, Sheen A, Farzin M, Toon CW, Turchini J, Gill AJ. Loss of INI1 expression in colorectal carcinoma is associated with high tumor grade, poor survival, BRAFV600E mutation, and mismatch repair deficiency. Hum Pathol 2016; 55:83-90. [PMID: 27184481 DOI: 10.1016/j.humpath.2016.04.018] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2016] [Revised: 04/14/2016] [Accepted: 04/22/2016] [Indexed: 12/15/2022]
Abstract
SMARCB1 is a tumor suppressor gene that encodes for the protein INI1. SMARCB1 is commonly inactivated and INI1 correspondingly shows loss of expression in a range of malignant neoplasms including rhabdoid tumors, renal medullary carcinomas, and epithelioid sarcomas. Loss of INI1 expression has recently been reported in occasional gastrointestinal adenocarcinomas. We sought to investigate the incidence and clinicopathological significance of INI1 loss in colorectal adenocarcinoma (CRC). Immunohistochemistry for INI1 was performed in tissue microarray (TMA) format on a well-characterized and unselected cohort of CRCs undergoing surgical resection. If staining was negative or equivocal in the TMA sections, immunohistochemistry was repeated on whole sections. Focal or widespread negative staining for INI1 was identified in whole sections from 14 (0.46%) of 3051 CRCs. In 7 (50%) of 14 negative cases, the loss of staining was focal, whereas the remainder were characterized by negative staining in all neoplastic cells in whole sections. In the cases with focal staining, loss of staining was frequently found in areas of poor differentiation. Global or focal INI1 loss was strongly associated with higher histological grade, larger tumor size and poor overall survival (P<.001). We conclude that INI1 loss occurs rarely (0.46% when screened by TMA) in CRC, where it is associated with higher grade, larger tumor size, poorer survival, mismatch repair deficiency, and BRAFV600E mutation.
Collapse
Affiliation(s)
- Jennifer Wang
- Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research, St Leonards, NSW, Australia 2065; Department of Anatomical Pathology, Royal North Shore Hospital, St Leonards NSW, Australia 2065
| | - Juliana Andrici
- Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research, St Leonards, NSW, Australia 2065; Department of Anatomical Pathology, Royal North Shore Hospital, St Leonards NSW, Australia 2065; Sydney Medical School, University of Sydney, NSW, Australia 2006
| | - Loretta Sioson
- Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research, St Leonards, NSW, Australia 2065
| | - Adele Clarkson
- Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research, St Leonards, NSW, Australia 2065; Department of Anatomical Pathology, Royal North Shore Hospital, St Leonards NSW, Australia 2065
| | - Amy Sheen
- Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research, St Leonards, NSW, Australia 2065
| | - Mahtab Farzin
- Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research, St Leonards, NSW, Australia 2065
| | - Christopher W Toon
- Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research, St Leonards, NSW, Australia 2065; Sydney Medical School, University of Sydney, NSW, Australia 2006; HistoPath Pathology, North Ryde, NSW, Australia 2113
| | - John Turchini
- Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research, St Leonards, NSW, Australia 2065; Department of Anatomical Pathology, Royal North Shore Hospital, St Leonards NSW, Australia 2065; Sydney Medical School, University of Sydney, NSW, Australia 2006
| | - Anthony J Gill
- Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research, St Leonards, NSW, Australia 2065; Department of Anatomical Pathology, Royal North Shore Hospital, St Leonards NSW, Australia 2065; Sydney Medical School, University of Sydney, NSW, Australia 2006.
| |
Collapse
|
|
26
|
Yakirevich E, Resnick MB, Mangray S, Wheeler M, Jackson CL, Lombardo KA, Lee J, Kim KM, Gill AJ, Wang K, Gowen K, Sun J, Miller VA, Stephens PJ, Ali SM, Ross JS, Safran H. Oncogenic ALK Fusion in Rare and Aggressive Subtype of Colorectal Adenocarcinoma as a Potential Therapeutic Target. Clin Cancer Res 2016; 22:3831-40. [DOI: 10.1158/1078-0432.ccr-15-3000] [Citation(s) in RCA: 83] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2015] [Accepted: 02/18/2016] [Indexed: 11/16/2022]
|
|
27
|
Knox RD, Luey N, Sioson L, Kedziora A, Clarkson A, Watson N, Toon CW, Cussigh C, Pincott S, Pillinger S, Salama Y, Evans J, Percy J, Schnitzler M, Engel A, Gill AJ. Medullary colorectal carcinoma revisited: a clinical and pathological study of 102 cases. Ann Surg Oncol 2015; 22:2988-96. [PMID: 25572685 DOI: 10.1245/s10434-014-4355-5] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2014] [Indexed: 12/11/2022]
Abstract
AIM Medullary carcinoma is a recently described subtype of mismatch repair deficient (MMRd) colorectal carcinoma (CRC) which, despite being poorly differentiated by traditional morphological criteria, has been reported to have a good prognosis. We investigated the pathological and clinical features of medullary CRC in an unselected cohort of CRCs undergoing surgical resection. METHODS All CRCs resected within a single health district database from 1998 to 2012 were categorized prospectively and underwent retrospective review to identify 91 medullary CRCs, with 11 additional cases from 2013 to 2014. Strict criteria were employed to diagnose medullary carcinoma requiring both MMRd and greater than 90 % of the tumor to demonstrate typical morphology, including solid growth. The demographic and pathological features, as well as all-cause survival, were compared with other CRCs, and specifically to other MMRd CRCs. RESULTS From 1998 to 2012, 91 of 3,295 CRCs (2.8 %) were of the medullary type. Medullary CRC was more likely to arise in females than males (3.3:1; p < 0.0001), the elderly (mean age 77 vs. 71 years; p < 0.001), and the right colon (86 %; p < 0.0001). All medullary CRCs demonstrated MMR deficiency (considered an inclusion criteria) and 86 % were BRAFV600E-mutated (p < 0.0001). Thirty-day mortality after resection was higher in medullary CRC (4.6 vs. 1.7 %; p = 0.049). On univariate analysis, survival was not better than well-differentiated or other MMRd tumors. However, using a multivariate model, a medullary phenotype was protective (hazard ratio of death 0.54, 95 % CI 0.30-0.96; p = 0.037). CONCLUSIONS Medullary CRC is more common than previously reported, frequently presents with locally advanced disease, and may be associated with higher mortality at 30 days after resection. Despite this, when strict criteria are used for diagnosis, the overall survival is favorable when compared with CRCs with equivalent demographic and pathological characteristics.
Collapse
Affiliation(s)
- Robert D Knox
- Sydney Medical School, University of Sydney, Sydney, NSW, Australia
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|