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McAfee JL, Scarborough R, Jia XS, Azzato EM, Astbury C, Ronen S, Andea AA, Billings SD, Ko JS. Combined utility of p16 and BRAF V600E in the evaluation of spitzoid tumors: Superiority to PRAME and correlation with FISH. J Cutan Pathol 2023; 50:155-168. [PMID: 36261329 PMCID: PMC10099989 DOI: 10.1111/cup.14342] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 09/16/2022] [Accepted: 10/15/2022] [Indexed: 01/24/2023]
Abstract
BACKGROUND Spitzoid melanocytic neoplasms are diagnostically challenging; criteria for malignancy continue to evolve. The ability to predict chromosomal abnormalities with immunohistochemistry (IHC) could help select cases requiring chromosomal evaluation. METHODS Fluorescence in situ hybridization (FISH)-tested spitzoid neoplasms at our institution (2013-2021) were reviewed. p16, BRAF V600E, and preferentially expressed antigen in melanoma (PRAME) IHC results were correlated with FISH. RESULTS A total of 174 cases (1.9F:1M, median age 28 years; range, 5 months-74 years) were included; final diagnoses: Spitz nevus (11%), atypical Spitz tumor (47%), spitzoid dysplastic nevus (9%), and spitzoid melanoma (32%). Sixty (34%) were FISH positive, most commonly with absolute 6p25 gain (RREB1 > 2). Dermal mitotic count was the only clinicopathologic predictor of FISH. Among IHC-stained cases, p16 was lost in 55 of 134 cases (41%); loss correlated with FISH positive (p < 0.001, Fisher exact test). BRAF V600E (14/88, 16%) and PRAME (15/56, 27%) expression did not correlate with FISH alone (p = 0.242 and p = 0.359, respectively, Fisher exact test). When examined together, however, p16-retained/BRAF V600E-negative lesions had low FISH-positive rates (5/37, 14%; 4/37, 11% not counting isolated MYB loss); all other marker combinations had high rates (56%-75% of cases; p < 0.001). CONCLUSIONS p16/BRAF V600E IHC predicts FISH results. "Low-risk" lesions (p16+ /BRAF V600E- ) uncommonly have meaningful FISH abnormalities (11%). PRAME may have limited utility in this setting.
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Affiliation(s)
- John L McAfee
- Department of Anatomic Pathology, Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | | | - Xuefei Sophia Jia
- Quantitative Health Sciences, Cleveland Clinic, Cleveland, Ohio, USA
| | - Elizabeth M Azzato
- Department of Molecular Pathology and Cytogenetics, Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Caroline Astbury
- Department of Molecular Pathology and Cytogenetics, Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Shira Ronen
- Department of Anatomic Pathology, Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Aleodor A Andea
- Department of Molecular Genetic Pathology and Dermatopathology, University of Michigan, Ann Arbor, Michigan, USA
| | - Steven D Billings
- Department of Anatomic Pathology, Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Jennifer S Ko
- Department of Anatomic Pathology, Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, Ohio, USA
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Novel Biomarkers and Druggable Targets in Advanced Melanoma. Cancers (Basel) 2021; 14:cancers14010081. [PMID: 35008245 PMCID: PMC8750474 DOI: 10.3390/cancers14010081] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 12/13/2021] [Accepted: 12/21/2021] [Indexed: 01/05/2023] Open
Abstract
Immunotherapy with Ipilimumab or antibodies against programmed death (ligand) 1 (anti-PD1/PDL1), targeted therapies with BRAF-inhibitors (anti-BRAF) and their combinations significantly changed melanoma treatment options in both primary, adjuvant and metastatic setting, allowing for a cure, or at least long-term survival, in most patients. However, up to 50% of those with advance or metastatic disease still have no significant benefit from such innovative therapies, and clinicians are not able to discriminate in advance neither who is going to respond and for how long nor who is going to develop collateral effects and which ones. However, druggable targets, as well as affordable and reliable biomarkers are needed to personalize resources at a single-patient level. In this manuscript, different molecules, genes, cells, pathways and even combinatorial algorithms or scores are included in four biomarker chapters (molecular, immunological, peripheral and gut microbiota) and reviewed in order to evaluate their role in indicating a patient’s possible response to treatment or development of toxicities.
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Helgadottir H, Ghiorzo P, van Doorn R, Puig S, Levin M, Kefford R, Lauss M, Queirolo P, Pastorino L, Kapiteijn E, Potrony M, Carrera C, Olsson H, Höiom V, Jönsson G. Efficacy of novel immunotherapy regimens in patients with metastatic melanoma with germline CDKN2A mutations. J Med Genet 2020; 57:316-321. [PMID: 30291219 PMCID: PMC7231460 DOI: 10.1136/jmedgenet-2018-105610] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Revised: 08/23/2018] [Accepted: 09/11/2018] [Indexed: 01/30/2023]
Abstract
BACKGROUND Inherited CDKN2A mutation is a strong risk factor for cutaneous melanoma. Moreover, carriers have been found to have poor melanoma-specific survival. In this study, responses to novel immunotherapy agents in CDKN2A mutation carriers with metastatic melanoma were evaluated. METHODS CDKN2A mutation carriers that have developed metastatic melanoma and undergone immunotherapy treatments were identified among carriers enrolled in follow-up studies for familial melanoma. The carriers' responses were compared with responses reported in phase III clinical trials for CTLA-4 and PD-1 inhibitors. From publicly available data sets, melanomas with somatic CDKN2A mutation were analysed for association with tumour mutational load. RESULTS Eleven of 19 carriers (58%) responded to the therapy, a significantly higher frequency than observed in clinical trials (p=0.03, binomial test against an expected rate of 37%). Further, 6 of the 19 carriers (32%) had complete response, a significantly higher frequency than observed in clinical trials (p=0.01, binomial test against an expected rate of 7%). In 118 melanomas with somatic CDKN2A mutations, significantly higher total numbers of mutations were observed compared with 761 melanomas without CDKN2A mutation (Wilcoxon test, p<0.001). CONCLUSION Patients with CDKN2A mutated melanoma may have improved immunotherapy responses due to increased tumour mutational load, resulting in more neoantigens and stronger antitumorous immune responses.
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Affiliation(s)
- Hildur Helgadottir
- Department of Oncology Pathology, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden
| | - Paola Ghiorzo
- Department of Internal Medicine and Medical Specialties, University of Genoa and Genetics of Rare Cancers, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | | | - Susana Puig
- Melanoma Unit, Dermatology Department, Hospital Clinic de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Raras, Instituto de Salud Carlos III, Barcelona, Spain
| | - Max Levin
- Department of Oncology, The Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden
| | - Richard Kefford
- Department of Clinical Medicine, Westmead Hospital and Macquarie University, Sydney, New South Wales, Australia
| | - Martin Lauss
- Department of Oncology, Clinical Sciences Lund, Lund University and Skåne University Hospital, Lund, Sweden.
| | - Paola Queirolo
- Department of Medical Oncology, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Lorenza Pastorino
- Department of Internal Medicine and Medical Specialties, University of Genoa and Genetics of Rare Cancers, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Ellen Kapiteijn
- Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands
| | - Miriam Potrony
- Melanoma Unit, Dermatology Department, Hospital Clinic de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Raras, Instituto de Salud Carlos III, Barcelona, Spain
| | - Cristina Carrera
- Melanoma Unit, Dermatology Department, Hospital Clinic de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Raras, Instituto de Salud Carlos III, Barcelona, Spain
| | - Håkan Olsson
- Department of Oncology, Clinical Sciences Lund, Lund University and Skåne University Hospital, Lund, Sweden.
| | - Veronica Höiom
- Department of Oncology Pathology, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden
| | - Göran Jönsson
- Department of Oncology, Clinical Sciences Lund, Lund University and Skåne University Hospital, Lund, Sweden.
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DeLeon TT, Almquist DR, Kipp BR, Langlais BT, Mangold A, Winters JL, Kosiorek HE, Joseph RW, Dronca RS, Block MS, McWilliams RR, Kottschade LA, Rumilla KM, Voss JS, Seetharam M, Sekulic A, Markovic SN, Bryce AH. Assessment of clinical outcomes with immune checkpoint inhibitor therapy in melanoma patients with CDKN2A and TP53 pathogenic mutations. PLoS One 2020; 15:e0230306. [PMID: 32196516 PMCID: PMC7083309 DOI: 10.1371/journal.pone.0230306] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Accepted: 02/27/2020] [Indexed: 12/27/2022] Open
Abstract
Background CDKN2A and TP53 mutations are recurrent events in melanoma, occurring in 13.3% and 15.1% of cases respectively and are associated with poorer outcomes. It is unclear what effect CDKN2A and TP53 mutations have on the clinical outcomes of patients treated with checkpoint inhibitors. Methods All patients with cutaneous melanoma or melanoma of unknown primary who received checkpoint inhibitor therapy and underwent genomic profiling with the 50-gene Mayo Clinic solid tumor targeted cancer gene panel were included. Patients were stratified according to the presence or absence of mutations in BRAF, NRAS, CDKN2A, and TP53. Patients without mutations in any of these genes were termed quadruple wild type (QuadWT). Clinical outcomes including median time to progression (TTP), median overall survival (OS), 6-month and 12-month OS, 6-month and 12-month without progression, ORR and disease control rate (DCR) were analyzed according to the mutational status of CDKN2A, TP53 and QuadWT. Results A total of 102 patients were included in this study of which 14 had mutations of CDKN2A (CDKN2Amut), 21 had TP53 mutations (TP53mut), and 12 were QuadWT. TP53mut, CDKN2Amut and QuadWT mutational status did not impact clinical outcomes including median TTP, median OS, 6-month and 12-month OS, 6-month and 12-month without progression, ORR and DCR. There was a trend towards improved median TTP and DCR in CDKN2Amut cohort and a trend towards worsened median TTP in the QuadWT cohort. Conclusion Cell cycle regulators such as TP53 and CDKN2A do not appear to significantly alter clinical outcomes when immune checkpoint inhibitors are used.
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Affiliation(s)
- Thomas T. DeLeon
- Department of Hematology & Oncology, Mayo Clinic Arizona, Scottsdale, Arizona, United States of America
| | - Daniel R. Almquist
- Department of Hematology & Oncology, Mayo Clinic Arizona, Scottsdale, Arizona, United States of America
| | - Benjamin R. Kipp
- Department of Laboratory Medicine and Pathology, Mayo Clinic Rochester, Rochester, Minnesota, United States of America
| | - Blake T. Langlais
- Department of Biostatistics, Mayo Clinic Arizona, Scottsdale, Arizona, United States of America
| | - Aaron Mangold
- Department of Dermatology, Mayo Clinic Arizona, Scottsdale, Arizona, United States of America
| | - Jennifer L. Winters
- Department of Laboratory Medicine and Pathology, Mayo Clinic Rochester, Rochester, Minnesota, United States of America
| | - Heidi E. Kosiorek
- Department of Biostatistics, Mayo Clinic Arizona, Scottsdale, Arizona, United States of America
| | - Richard W. Joseph
- Department of Hematology & Oncology, Mayo Clinic Rochester, Rochester, Minnesota, United States of America
| | - Roxana S. Dronca
- Department of Hematology & Oncology, Mayo Clinic Rochester, Rochester, Minnesota, United States of America
| | - Matthew S. Block
- Department of Hematology & Oncology, Mayo Clinic Rochester, Rochester, Minnesota, United States of America
| | - Robert R. McWilliams
- Department of Hematology & Oncology, Mayo Clinic Rochester, Rochester, Minnesota, United States of America
| | - Lisa A. Kottschade
- Department of Hematology & Oncology, Mayo Clinic Rochester, Rochester, Minnesota, United States of America
| | - Kandelaria M. Rumilla
- Department of Laboratory Medicine and Pathology, Mayo Clinic Rochester, Rochester, Minnesota, United States of America
| | - Jesse S. Voss
- Department of Laboratory Medicine and Pathology, Mayo Clinic Rochester, Rochester, Minnesota, United States of America
| | - Mahesh Seetharam
- Department of Hematology & Oncology, Mayo Clinic Arizona, Scottsdale, Arizona, United States of America
| | - Aleksandar Sekulic
- Department of Dermatology, Mayo Clinic Arizona, Scottsdale, Arizona, United States of America
- Mayo Clinic Cancer Center, Phoenix, Arizona, United States of America
| | - Svetomir N. Markovic
- Department of Hematology & Oncology, Mayo Clinic Rochester, Rochester, Minnesota, United States of America
| | - Alan H. Bryce
- Department of Hematology & Oncology, Mayo Clinic Arizona, Scottsdale, Arizona, United States of America
- * E-mail:
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McEvoy CR, Xu H, Smith K, Etemadmoghadam D, San Leong H, Choong DY, Byrne DJ, Iravani A, Beck S, Mileshkin L, Tothill RW, Bowtell DD, Bates BM, Nastevski V, Browning J, Bell AH, Khoo C, Desai J, Fellowes AP, Fox SB, Prall OW. Profound MEK inhibitor response in a cutaneous melanoma harboring a GOLGA4-RAF1 fusion. J Clin Invest 2019; 129:1940-1945. [PMID: 30835257 PMCID: PMC6486352 DOI: 10.1172/jci123089] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2018] [Accepted: 02/26/2019] [Indexed: 12/11/2022] Open
Abstract
BRAF and CRAF are critical components of the MAPK signaling pathway which is activated in many cancer types. In approximately 1% of melanomas, BRAF or CRAF are activated through structural arrangements. We describe here a metastatic melanoma with a GOLGA4-RAF1 fusion and pathogenic variants in CTNNB1 and CDKN2A. Anti-CTLA4/anti-PD1 combination immunotherapy failed to control tumor progression. In the absence of other actionable variants the patient was administered MEK inhibitor therapy on the basis of its potential action against RAF1 fusions. This resulted in a profound and clinically significant response. We demonstrated that GOLGA4-RAF1 expression was associated with ERK activation, elevated expression of the RAS/RAF downstream co-effector ETV5, and a high Ki67 index. These findings provide a rationale for the dramatic response to targeted therapy. This study shows that thorough molecular characterization of treatment-resistant cancers can identify therapeutic targets and personalize management, leading to improved patient outcomes.
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Affiliation(s)
- Christopher R. McEvoy
- Department of Pathology, and
- Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Australia
| | - Huiling Xu
- Department of Pathology, and
- Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Australia
- Clinical Pathology, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Australia
| | | | | | | | | | | | - Amir Iravani
- Department of Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Australia
| | - Sophie Beck
- Department of Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Australia
| | - Linda Mileshkin
- Department of Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Australia
- Sir Peter MacCallum Department of Oncology, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Australia
| | - Richard W. Tothill
- Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Australia
- Clinical Pathology, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Australia
| | - David D. Bowtell
- Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Australia
- Sir Peter MacCallum Department of Oncology, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Australia
| | | | | | | | | | - Chloe Khoo
- Department of Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Australia
| | - Jayesh Desai
- Department of Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Australia
- Sir Peter MacCallum Department of Oncology, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Australia
- Department of Surgery, St Vincent’s Hospital, Fitzroy, Australia
- Clinical School, Austin Health, Heidelberg, Australia
- Department of Surgery, Royal Melbourne Hospital, Parkville, Australia
| | - Andrew P. Fellowes
- Department of Pathology, and
- Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Australia
| | - Stephen B. Fox
- Department of Pathology, and
- Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Australia
- Clinical Pathology, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Australia
- Sir Peter MacCallum Department of Oncology, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Australia
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Thrane K, Eriksson H, Maaskola J, Hansson J, Lundeberg J. Spatially Resolved Transcriptomics Enables Dissection of Genetic Heterogeneity in Stage III Cutaneous Malignant Melanoma. Cancer Res 2018; 78:5970-5979. [PMID: 30154148 DOI: 10.1158/0008-5472.can-18-0747] [Citation(s) in RCA: 199] [Impact Index Per Article: 28.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2018] [Revised: 07/03/2018] [Accepted: 08/23/2018] [Indexed: 11/16/2022]
Abstract
Cutaneous malignant melanoma (melanoma) is characterized by a high mutational load, extensive intertumoral and intratumoral genetic heterogeneity, and complex tumor microenvironment (TME) interactions. Further insights into the mechanisms underlying melanoma are crucial for understanding tumor progression and responses to treatment. Here we adapted the technology of spatial transcriptomics (ST) to melanoma lymph node biopsies and successfully sequenced the transcriptomes of over 2,200 tissue domains. Deconvolution combined with traditional approaches for dimensional reduction of transcriptome-wide data enabled us to both visualize the transcriptional landscape within the tissue and identify gene expression profiles linked to specific histologic entities. Our unsupervised analysis revealed a complex spatial intratumoral composition of melanoma metastases that was not evident through morphologic annotation. Each biopsy showed distinct gene expression profiles and included examples of the coexistence of multiple melanoma signatures within a single tumor region as well as shared profiles for lymphoid tissue characterized according to their spatial location and gene expression profiles. The lymphoid area in close proximity to the tumor region displayed a specific expression pattern, which may reflect the TME, a key component to fully understanding tumor progression. In conclusion, using the ST technology to generate gene expression profiles reveals a detailed landscape of melanoma metastases. This should inspire researchers to integrate spatial information into analyses aiming to identify the factors underlying tumor progression and therapy outcome.Significance: Applying ST technology to gene expression profiling in melanoma lymph node metastases reveals a complex transcriptional landscape in a spatial context, which is essential for understanding the multiple components of tumor progression and therapy outcome. Cancer Res; 78(20); 5970-9. ©2018 AACR.
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Affiliation(s)
- Kim Thrane
- Department of Gene Technology, KTH Royal Institute of Technology, SciLifeLab, Stockholm, Sweden
| | - Hanna Eriksson
- Department of Oncology-Pathology, Karolinska Institutet, SE-17176 Stockholm, Sweden
- Department of Oncology, Karolinska University Hospital, SE-17176 Stockholm, Sweden
| | - Jonas Maaskola
- Department of Gene Technology, KTH Royal Institute of Technology, SciLifeLab, Stockholm, Sweden
| | - Johan Hansson
- Department of Oncology-Pathology, Karolinska Institutet, SE-17176 Stockholm, Sweden
- Department of Oncology, Karolinska University Hospital, SE-17176 Stockholm, Sweden
| | - Joakim Lundeberg
- Department of Gene Technology, KTH Royal Institute of Technology, SciLifeLab, Stockholm, Sweden.
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Eisenstein A, Gonzalez EC, Raghunathan R, Xu X, Wu M, McLean EO, McGee J, Ryu B, Alani RM. Emerging Biomarkers in Cutaneous Melanoma. Mol Diagn Ther 2018; 22:203-218. [PMID: 29411301 DOI: 10.1007/s40291-018-0318-z] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Earlier identification of aggressive melanoma remains a goal in the field of melanoma research. With new targeted and immune therapies that have revolutionized the care of patients with melanoma, the ability to predict progression and monitor or predict response to therapy has become the new focus of research into biomarkers in melanoma. In this review, promising biomarkers are highlighted. These biomarkers have been used to diagnose melanoma as well as predict progression to advanced disease and response to therapy. The biomarkers take various forms, including protein expression at the level of tissue, genetic mutations of cancer cells, and detection of circulating DNA. First, a brief description is provided about the conventional tissue markers used to stage melanoma, including tumor depth. Next, protein biomarkers, which provide both diagnostic and prognostic information, are described. This is followed by a discussion of important genetic mutations, microRNA, and epigenetic modifications that can provide therapeutic and prognostic material. Finally, emerging serologic biomarkers are reviewed, including circulating melanoma cells and exosomes. Overall the goal is to identify biomarkers that aid in the earlier identification and improved treatment of aggressive melanoma.
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Affiliation(s)
- Anna Eisenstein
- Department of Dermatology, Boston University School of Medicine, 609 Albany Street, Boston, MA, 02118, USA
| | - Estela Chen Gonzalez
- Department of Dermatology, Boston University School of Medicine, 609 Albany Street, Boston, MA, 02118, USA
| | - Rekha Raghunathan
- Department of Dermatology, Boston University School of Medicine, 609 Albany Street, Boston, MA, 02118, USA
| | - Xixi Xu
- Department of Dermatology, Boston University School of Medicine, 609 Albany Street, Boston, MA, 02118, USA
| | - Muzhou Wu
- Department of Dermatology, Boston University School of Medicine, 609 Albany Street, Boston, MA, 02118, USA
| | - Emily O McLean
- Department of Dermatology, Boston University School of Medicine, 609 Albany Street, Boston, MA, 02118, USA
| | - Jean McGee
- Department of Dermatology, Boston University School of Medicine, 609 Albany Street, Boston, MA, 02118, USA
| | - Byungwoo Ryu
- Department of Dermatology, Boston University School of Medicine, 609 Albany Street, Boston, MA, 02118, USA.
| | - Rhoda M Alani
- Department of Dermatology, Boston University School of Medicine, 609 Albany Street, Boston, MA, 02118, USA.
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Pejkova S, Dzokic G, Tudzarova-Gjorgova S, Panov S. Molecular Biology and Genetic Mechanisms in the Progression of the Malignant Skin Melanoma. ACTA ACUST UNITED AC 2017; 37:89-97. [PMID: 27883322 DOI: 10.1515/prilozi-2016-0021] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Malignant skin melanoma is a tumor deriving from transformed skin melanocytes as a result of complex interactions between genetic and environmental factors. This melanoma has a potential to metastasize early and very often it is resistant to the existing modalities of the systemic therapy. As in any other neoplasms, certain types of melanoma may skip certain stages of progression. The progression from one stage to another is accompanied by specific biological changes. Several key changes in the melanoma tumorogenesis influence the regulation of the cell proliferation and vitality, including the RAS-RAF-ERK, PI3K-AKT, and p16INK4/CDK4/RB pathways. A key role in the dissreguarity of the RAS-RAF-ERK (MAPK) pathway in the malignant melanoma development have been demonstrated by many studies. To date, the molecular genetic alterations during melanoma development have been partially known. In the pathogenesis of the malignant melanoma, there are mutations of various genes such as NRAS, BRAF, and PTEN and mutations and deletions of CDKN2A. In the past years, great advance has been made in the insights of the molecular aspects of the melanoma pathogenesis. However, this field yet poses a challenge to discover new details about the melanoma molecular characteristics. The research results are focused towards the improvement of the melanoma patients prognosis by introducing personalized targeted therapy.
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Helgadottir H, Höiom V, Tuominen R, Nielsen K, Jönsson G, Olsson H, Hansson J. Germline CDKN2A Mutation Status and Survival in Familial Melanoma Cases. J Natl Cancer Inst 2016; 108:djw135. [PMID: 27287845 DOI: 10.1093/jnci/djw135] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2015] [Accepted: 04/20/2016] [Indexed: 01/24/2023] Open
Abstract
BACKGROUND Germline mutations in CDKN2A have been associated with increased risk of melanoma and tobacco-related cancers in respiratory and upper digestive tissues. In CDKN2A wild-type (wt) melanoma families, other known high-risk, melanoma-predisposing mutations are rare, and no increased risk has been observed for nonskin cancers in this group. This study is the first to compare survival in germline CDKN2A mutated (mut) and nonmutated melanoma cases. METHODS Melanoma-prone families participating in this study were identified through a nationwide predictive program starting in 1987. Information on cancer diagnoses (types, stages, and dates) and deaths (causes and dates) were obtained through the Swedish Cancer Registry and Cause of Death Registry. Kaplan Meier and Cox proportional hazards regression models were used to assess survival in CDKN2A(mut) (n = 96) and CDKN2A(wt) (n = 377) familial melanoma cases and in matched sporadic melanoma cases (n = 1042). All statistical tests were two-sided. RESULTS When comparing CDKN2A(mut) and CDKN2A(wt) melanoma cases, after adjusting for age, sex, and T classification, CDKN2A(mut) had worse survival than melanoma (hazard ratio [HR] = 2.50, 95% confidence interval [CI] = 1.49 to 4.21) and than nonmelanoma cancers (HR = 7.77, 95% CI = 3.65 to 16.51). Compared with matched sporadic cases, CDKN2A(mut) cases had statistically significantly worse survival from both melanoma and nonmelanoma cancers while no differences in survival were seen in CDKN2A(wt) compared with sporadic cases. CONCLUSIONS CDKN2A(mut) cases had statistically significantly worse survival than nonmelanoma cancers and, intriguingly, also from melanoma, compared with melanoma cases with no CDKN2A mutations. Further studies are required to elucidate possible mechanisms behind increased carcinogen susceptibility and the more aggressive melanoma phenotype in CDKN2A mutation carriers.
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Affiliation(s)
- Hildur Helgadottir
- Affiliations of authors: Department of Oncology-Pathology, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden (HH, VH, RT, JH); Department of Oncology, Clinical Sciences Lund, Lund University and Skåne University Hospital (GJ, HO); Department of Dermatology, Clinical Sciences Lund, Lund University and Helsingborg Hospital (KN)
| | - Veronica Höiom
- Affiliations of authors: Department of Oncology-Pathology, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden (HH, VH, RT, JH); Department of Oncology, Clinical Sciences Lund, Lund University and Skåne University Hospital (GJ, HO); Department of Dermatology, Clinical Sciences Lund, Lund University and Helsingborg Hospital (KN)
| | - Rainer Tuominen
- Affiliations of authors: Department of Oncology-Pathology, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden (HH, VH, RT, JH); Department of Oncology, Clinical Sciences Lund, Lund University and Skåne University Hospital (GJ, HO); Department of Dermatology, Clinical Sciences Lund, Lund University and Helsingborg Hospital (KN)
| | - Kari Nielsen
- Affiliations of authors: Department of Oncology-Pathology, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden (HH, VH, RT, JH); Department of Oncology, Clinical Sciences Lund, Lund University and Skåne University Hospital (GJ, HO); Department of Dermatology, Clinical Sciences Lund, Lund University and Helsingborg Hospital (KN)
| | - Göran Jönsson
- Affiliations of authors: Department of Oncology-Pathology, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden (HH, VH, RT, JH); Department of Oncology, Clinical Sciences Lund, Lund University and Skåne University Hospital (GJ, HO); Department of Dermatology, Clinical Sciences Lund, Lund University and Helsingborg Hospital (KN)
| | - Håkan Olsson
- Affiliations of authors: Department of Oncology-Pathology, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden (HH, VH, RT, JH); Department of Oncology, Clinical Sciences Lund, Lund University and Skåne University Hospital (GJ, HO); Department of Dermatology, Clinical Sciences Lund, Lund University and Helsingborg Hospital (KN)
| | - Johan Hansson
- Affiliations of authors: Department of Oncology-Pathology, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden (HH, VH, RT, JH); Department of Oncology, Clinical Sciences Lund, Lund University and Skåne University Hospital (GJ, HO); Department of Dermatology, Clinical Sciences Lund, Lund University and Helsingborg Hospital (KN)
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10
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McCubrey JA, Rakus D, Gizak A, Steelman LS, Abrams SL, Lertpiriyapong K, Fitzgerald TL, Yang LV, Montalto G, Cervello M, Libra M, Nicoletti F, Scalisi A, Torino F, Fenga C, Neri LM, Marmiroli S, Cocco L, Martelli AM. Effects of mutations in Wnt/β-catenin, hedgehog, Notch and PI3K pathways on GSK-3 activity-Diverse effects on cell growth, metabolism and cancer. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2016; 1863:2942-2976. [PMID: 27612668 DOI: 10.1016/j.bbamcr.2016.09.004] [Citation(s) in RCA: 116] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/16/2016] [Revised: 08/14/2016] [Accepted: 09/02/2016] [Indexed: 02/07/2023]
Abstract
Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase that participates in an array of critical cellular processes. GSK-3 was first characterized as an enzyme that phosphorylated and inactivated glycogen synthase. However, subsequent studies have revealed that this moon-lighting protein is involved in numerous signaling pathways that regulate not only metabolism but also have roles in: apoptosis, cell cycle progression, cell renewal, differentiation, embryogenesis, migration, regulation of gene transcription, stem cell biology and survival. In this review, we will discuss the roles that GSK-3 plays in various diseases as well as how this pivotal kinase interacts with multiple signaling pathways such as: PI3K/PTEN/Akt/mTOR, Ras/Raf/MEK/ERK, Wnt/beta-catenin, hedgehog, Notch and TP53. Mutations that occur in these and other pathways can alter the effects that natural GSK-3 activity has on regulating these signaling circuits that can lead to cancer as well as other diseases. The novel roles that microRNAs play in regulation of the effects of GSK-3 will also be evaluated. Targeting GSK-3 and these other pathways may improve therapy and overcome therapeutic resistance.
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Affiliation(s)
- James A McCubrey
- Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University Greenville, NC 27858, USA.
| | - Dariusz Rakus
- Department of Animal Molecular Physiology, Institute of Experimental Biology, Wroclaw University, Wroclaw, Poland
| | - Agnieszka Gizak
- Department of Animal Molecular Physiology, Institute of Experimental Biology, Wroclaw University, Wroclaw, Poland
| | - Linda S Steelman
- Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University Greenville, NC 27858, USA
| | - Steve L Abrams
- Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University Greenville, NC 27858, USA
| | - Kvin Lertpiriyapong
- Department of Comparative Medicine, Brody School of Medicine at East Carolina University, USA
| | - Timothy L Fitzgerald
- Department of Surgery, Brody School of Medicine at East Carolina University, USA
| | - Li V Yang
- Department of Internal Medicine, Hematology/Oncology Section, Brody School of Medicine at East Carolina University, USA
| | - Giuseppe Montalto
- Biomedical Department of Internal Medicine and Specialties, University of Palermo, Palermo, Italy; Consiglio Nazionale delle Ricerche, Istituto di Biomedicina e Immunologia Molecolare "Alberto Monroy", Palermo, Italy
| | - Melchiorre Cervello
- Consiglio Nazionale delle Ricerche, Istituto di Biomedicina e Immunologia Molecolare "Alberto Monroy", Palermo, Italy
| | - Massimo Libra
- Department of Bio-medical Sciences, University of Catania, Catania, Italy
| | | | - Aurora Scalisi
- Unit of Oncologic Diseases, ASP-Catania, Catania 95100, Italy
| | - Francesco Torino
- Department of Systems Medicine, Chair of Medical Oncology, Tor Vergata University of Rome, Rome, Italy
| | - Concettina Fenga
- Department of Biomedical, Odontoiatric, Morphological and Functional Images, Occupational Medicine Section - Policlinico "G. Martino" - University of Messina, Messina 98125, Italy
| | - Luca M Neri
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
| | - Sandra Marmiroli
- Department of Surgery, Medicine, Dentistry and Morphology, University of Modena and Reggio Emilia, Modena, Italy
| | - Lucio Cocco
- Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy
| | - Alberto M Martelli
- Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy
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11
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Xu S, Wang H, Pan H, Shi Y, Li T, Ge S, Jia R, Zhang H, Fan X. ANRIL lncRNA triggers efficient therapeutic efficacy by reprogramming the aberrant INK4-hub in melanoma. Cancer Lett 2016; 381:41-8. [PMID: 27461581 DOI: 10.1016/j.canlet.2016.07.024] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Revised: 06/22/2016] [Accepted: 07/19/2016] [Indexed: 01/09/2023]
Abstract
Melanoma is an extremely aggressive disease with rapid progression, high metastatic potential and recurrence. Simultaneous correction of multiple tumor-specific gene abnormalities has become an attractive approach for developing therapeutics to treat melanoma. To potentiate anti-melanoma activity, we tested a "domino effect-like" therapeutic approach by uniquely targeting one defect and automatically triggering the endogenous corrections of other defects. Using this strategy, in a suspicious INK4b-ARF-INK4a gene cluster at chromosome 9p21, aberrant INK4a and INK4b defects were simultaneously endogenously auto-corrected after targeting the suppression of abnormal ANRIL lncRNA. In cell culture, this treatment significantly reduced the tumor metastatic capacity and tumor formation compared with absence of treatment. In animals harboring tumor xenografts, this therapeutic approach significantly inhibited tumor growth and reduced the tumor weight. Our results reveal a novel therapeutic strategy that significantly potentiates anti-melanoma efficiency by reprogramming the aberrant INK4-hub.
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Affiliation(s)
- Shiqiong Xu
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Huixue Wang
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Hui Pan
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Yingyun Shi
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Tianyuan Li
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Shengfang Ge
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Renbing Jia
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - He Zhang
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China.
| | - Xianqun Fan
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China.
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12
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Gandolfi G, Dallaglio K, Longo C, Moscarella E, Lallas A, Alfano R, Argenziano G, Ciarrocchi A. Contemporary and potential future molecular diagnosis of melanoma. Expert Rev Mol Diagn 2016; 16:975-85. [DOI: 10.1080/14737159.2016.1206473] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Affiliation(s)
- G. Gandolfi
- Laboratory of Translational Research, Arcispedale S. Maria Nuova-IRCCS, Reggio Emilia, Italy
| | - K. Dallaglio
- Laboratory of Translational Research, Arcispedale S. Maria Nuova-IRCCS, Reggio Emilia, Italy
| | - C. Longo
- Skin Cancer Unit, Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia, Italy
| | - E. Moscarella
- Skin Cancer Unit, Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia, Italy
| | - A. Lallas
- Skin Cancer Unit, Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia, Italy
| | - R. Alfano
- Surgery and Emergency Unit, Second University of Naples, Naples, Italy
| | - G. Argenziano
- Skin Cancer Unit, Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia, Italy
- Dermatology Unit, Second University of Naples, Naples, Italy
| | - A. Ciarrocchi
- Laboratory of Translational Research, Arcispedale S. Maria Nuova-IRCCS, Reggio Emilia, Italy
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13
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Hosler GA, Davoli T, Mender I, Litzner B, Choi J, Kapur P, Shay JW, Wang RC. A primary melanoma and its asynchronous metastasis highlight the role of BRAF, CDKN2A, and TERT. J Cutan Pathol 2015; 42:108-17. [PMID: 25407517 PMCID: PMC4470704 DOI: 10.1111/cup.12444] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2014] [Revised: 10/21/2014] [Accepted: 11/12/2014] [Indexed: 01/13/2023]
Abstract
BACKGROUND Alterations in pathways including BRAF, CDKN2A, and TERT contribute to the development of melanoma, but the sequence in which the genetic alterations occur and their prognostic significance remains unclear. To clarify the role of these pathways, we analyzed a primary melanoma and its metastasis. METHODS Immunohistochemistry for BRAF-V600E, Sanger sequencing of BRAF and the TERT promoter, fluorescence in-situ hybridization, and telomere analyses were performed on a primary melanoma and its asynchronous cerebellar metastasis. Using the log-rank test and Cox-proportional model, the cancer genome atlas (TCGA) cohort of melanomas was analyzed for the effect of BRAF mutation and CDKN2A loss on survival. RESULTS The primary melanoma expressed mutant BRAF-V600E and possessed a homozygous deletion of CDKN2A. In addition to these early defects, the metastatic lesion also possessed evidence of aneuploidy and an activating mutation of the TERT promoter. In the TCGA melanoma cohort, there was a non-significant trend toward poor prognosis in early stage cutaneous melanoma patients with concomitant BRAF mutation and CDKN2A loss. CONCLUSION BRAF mutation and CDKN2A loss occurred early and TERT promoter mutation later in a case of lethal metastatic melanoma. The effects of these pathways on survival warrant further investigation in early stage cutaneous melanoma patients.
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Affiliation(s)
- Gregory A. Hosler
- Department of Dermatology, UT Southwestern Medical Center, Dallas, TX
- ProPath, Dallas, TX
- Department of Pathology, UT Southwestern Medical Center, Dallas, TX
| | - Teresa Davoli
- Division of Genetics, Brigham and Women’s Hospital, Boston, MA
| | - Ilgen Mender
- Department of Cell Biology, UT Southwestern Medical Center, Dallas, TX
| | - Brandon Litzner
- Department of Dermatology, UT Southwestern Medical Center, Dallas, TX
| | - Jaehyuk Choi
- Department of Dermatology, Yale Medical School, New Haven, CT
| | - Payal Kapur
- Department of Pathology, UT Southwestern Medical Center, Dallas, TX
| | - Jerry W. Shay
- Department of Cell Biology, UT Southwestern Medical Center, Dallas, TX
| | - Richard C. Wang
- Department of Dermatology, UT Southwestern Medical Center, Dallas, TX
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14
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Ding L, Kim M, Kanchi KL, Dees ND, Lu C, Griffith M, Fenstermacher D, Sung H, Miller CA, Goetz B, Wendl MC, Griffith O, Cornelius LA, Linette GP, McMichael JF, Sondak VK, Fields RC, Ley TJ, Mulé JJ, Wilson RK, Weber JS. Clonal architectures and driver mutations in metastatic melanomas. PLoS One 2014; 9:e111153. [PMID: 25393105 PMCID: PMC4230926 DOI: 10.1371/journal.pone.0111153] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2014] [Accepted: 07/27/2014] [Indexed: 12/03/2022] Open
Abstract
To reveal the clonal architecture of melanoma and associated driver mutations, whole genome sequencing (WGS) and targeted extension sequencing were used to characterize 124 melanoma cases. Significantly mutated gene analysis using 13 WGS cases and 15 additional paired extension cases identified known melanoma genes such as BRAF, NRAS, and CDKN2A, as well as a novel gene EPHA3, previously implicated in other cancer types. Extension studies using tumors from another 96 patients discovered a large number of truncation mutations in tumor suppressors (TP53 and RB1), protein phosphatases (e.g., PTEN, PTPRB, PTPRD, and PTPRT), as well as chromatin remodeling genes (e.g., ASXL3, MLL2, and ARID2). Deep sequencing of mutations revealed subclones in the majority of metastatic tumors from 13 WGS cases. Validated mutations from 12 out of 13 WGS patients exhibited a predominant UV signature characterized by a high frequency of C->T transitions occurring at the 3′ base of dipyrimidine sequences while one patient (MEL9) with a hypermutator phenotype lacked this signature. Strikingly, a subclonal mutation signature analysis revealed that the founding clone in MEL9 exhibited UV signature but the secondary clone did not, suggesting different mutational mechanisms for two clonal populations from the same tumor. Further analysis of four metastases from different geographic locations in 2 melanoma cases revealed phylogenetic relationships and highlighted the genetic alterations responsible for differential drug resistance among metastatic tumors. Our study suggests that clonal evaluation is crucial for understanding tumor etiology and drug resistance in melanoma.
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Affiliation(s)
- Li Ding
- The Genome Institute, Washington University in St. Louis, St. Louis, Missouri, United States of America
- Department of Medicine, Washington University in St. Louis, St. Louis, Missouri, United States of America
- Department of Genetics, Washington University in St. Louis, St. Louis, Missouri, United States of America
- Siteman Cancer Center, Washington University in St. Louis, St. Louis, Missouri, United States of America
| | - Minjung Kim
- Donald A. Adam Comprehensive Melanoma Research Center, Moffitt Cancer Center, Tampa, Florida, United States of America
| | - Krishna L. Kanchi
- The Genome Institute, Washington University in St. Louis, St. Louis, Missouri, United States of America
| | - Nathan D. Dees
- The Genome Institute, Washington University in St. Louis, St. Louis, Missouri, United States of America
| | - Charles Lu
- The Genome Institute, Washington University in St. Louis, St. Louis, Missouri, United States of America
| | - Malachi Griffith
- The Genome Institute, Washington University in St. Louis, St. Louis, Missouri, United States of America
- Department of Genetics, Washington University in St. Louis, St. Louis, Missouri, United States of America
| | - David Fenstermacher
- Donald A. Adam Comprehensive Melanoma Research Center, Moffitt Cancer Center, Tampa, Florida, United States of America
| | - Hyeran Sung
- Donald A. Adam Comprehensive Melanoma Research Center, Moffitt Cancer Center, Tampa, Florida, United States of America
| | - Christopher A. Miller
- The Genome Institute, Washington University in St. Louis, St. Louis, Missouri, United States of America
| | - Brian Goetz
- Department of Surgery, Washington University in St. Louis, St. Louis, Missouri, United States of America
| | - Michael C. Wendl
- The Genome Institute, Washington University in St. Louis, St. Louis, Missouri, United States of America
| | - Obi Griffith
- The Genome Institute, Washington University in St. Louis, St. Louis, Missouri, United States of America
- Department of Medicine, Washington University in St. Louis, St. Louis, Missouri, United States of America
| | - Lynn A. Cornelius
- Department of Medicine, Washington University in St. Louis, St. Louis, Missouri, United States of America
- Department of Surgery, Washington University in St. Louis, St. Louis, Missouri, United States of America
| | - Gerald P. Linette
- Department of Medicine, Washington University in St. Louis, St. Louis, Missouri, United States of America
- Siteman Cancer Center, Washington University in St. Louis, St. Louis, Missouri, United States of America
| | - Joshua F. McMichael
- The Genome Institute, Washington University in St. Louis, St. Louis, Missouri, United States of America
| | - Vernon K. Sondak
- Donald A. Adam Comprehensive Melanoma Research Center, Moffitt Cancer Center, Tampa, Florida, United States of America
| | - Ryan C. Fields
- Siteman Cancer Center, Washington University in St. Louis, St. Louis, Missouri, United States of America
- Department of Surgery, Washington University in St. Louis, St. Louis, Missouri, United States of America
| | - Timothy J. Ley
- The Genome Institute, Washington University in St. Louis, St. Louis, Missouri, United States of America
- Department of Medicine, Washington University in St. Louis, St. Louis, Missouri, United States of America
- Siteman Cancer Center, Washington University in St. Louis, St. Louis, Missouri, United States of America
| | - James J. Mulé
- Donald A. Adam Comprehensive Melanoma Research Center, Moffitt Cancer Center, Tampa, Florida, United States of America
| | - Richard K. Wilson
- The Genome Institute, Washington University in St. Louis, St. Louis, Missouri, United States of America
- Department of Genetics, Washington University in St. Louis, St. Louis, Missouri, United States of America
- Siteman Cancer Center, Washington University in St. Louis, St. Louis, Missouri, United States of America
| | - Jeffrey S. Weber
- Donald A. Adam Comprehensive Melanoma Research Center, Moffitt Cancer Center, Tampa, Florida, United States of America
- * E-mail:
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15
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Marzese DM, Scolyer RA, Roqué M, Vargas-Roig LM, Huynh JL, Wilmott JS, Murali R, Buckland ME, Barkhoudarian G, Thompson JF, Morton DL, Kelly DF, Hoon DSB. DNA methylation and gene deletion analysis of brain metastases in melanoma patients identifies mutually exclusive molecular alterations. Neuro Oncol 2014; 16:1499-509. [PMID: 24968695 PMCID: PMC4201072 DOI: 10.1093/neuonc/nou107] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2013] [Accepted: 05/08/2014] [Indexed: 01/02/2023] Open
Abstract
BACKGROUND The brain is a common target of metastases for melanoma patients. Little is known about the genetic and epigenetic alterations in melanoma brain metastases (MBMs). Unraveling these molecular alterations is a key step in understanding their aggressive nature and identifying novel therapeutic targets. METHODS Genome-wide DNA methylation analyses of MBMs (n = 15) and normal brain tissues (n = 91) and simultaneous multigene DNA methylation and gene deletion analyses of metastatic melanoma tissues (99 MBMs and 43 extracranial metastases) were performed. BRAF and NRAS mutations were evaluated in MBMs by targeted sequencing. RESULTS MBMs showed significant epigenetic heterogeneity. RARB, RASSF1, ESR1, APC, PTEN, and CDH13 genes were frequently hypermethylated. Deletions were frequently detected in the CDKN2A/B locus. Of MBMs, 46.1% and 28.8% had BRAF and NRAS missense mutations, respectively. Compared with lung and liver metastases, MBMs exhibited higher frequency of CDH13 hypermethylation and CDKN2A/B locus deletion. Mutual exclusivity between hypermethylated genes and CDKN2A/B locus deletion identified 2 clinically relevant molecular subtypes of MBMs. CDKN2A/B deletions were associated with multiple MBMs and frequently hypermethylated genes with shorter time to brain metastasis. CONCLUSIONS Melanoma cells that colonize the brain harbor numerous genetically and epigenetically altered genes. This study presents an integrated genomic and epigenomic analysis that reveals MBM-specific molecular alterations and mutually exclusive molecular subtypes.
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Affiliation(s)
- Diego M Marzese
- Department of Molecular Oncology, John Wayne Cancer Institute, Santa Monica, California (D.M.M., J.L.H., D.S.B.H.); Department of Tissue Oncology and Diagnostic Pathology (R.A.S., M.E.B., J.F.T.) and Department of Melanoma and Surgical Oncology, Royal Prince Alfred Hospital, Sydney, Australia (J.F.T.); Sydney Medical School, The University of Sydney, Sydney, Australia (R.A.S., J.S.W., M.E.B., J.F.T.); Melanoma Institute Australia, Sydney, Australia (R.A.S., J.S.W.); Cellular and Molecular Biology Laboratory, Institute of Histology and Embryology, Mendoza, Argentina (M.R.); Tumor Biology Laboratory, Institute of Medicine and Experimental Biology of Cuyo, Mendoza, Argentina (L.M.V.-R.); Department of Pathology (R.M.), Center for Molecular Oncology (R.M.), and Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York (R.M.); Division of Surgical Oncology, John Wayne Cancer Institute, Santa Monica, California (D.L.M.); Brain Tumor Center, Saint John's Health Center, Santa Monica, California (G.B., D.F.K.)
| | - Richard A Scolyer
- Department of Molecular Oncology, John Wayne Cancer Institute, Santa Monica, California (D.M.M., J.L.H., D.S.B.H.); Department of Tissue Oncology and Diagnostic Pathology (R.A.S., M.E.B., J.F.T.) and Department of Melanoma and Surgical Oncology, Royal Prince Alfred Hospital, Sydney, Australia (J.F.T.); Sydney Medical School, The University of Sydney, Sydney, Australia (R.A.S., J.S.W., M.E.B., J.F.T.); Melanoma Institute Australia, Sydney, Australia (R.A.S., J.S.W.); Cellular and Molecular Biology Laboratory, Institute of Histology and Embryology, Mendoza, Argentina (M.R.); Tumor Biology Laboratory, Institute of Medicine and Experimental Biology of Cuyo, Mendoza, Argentina (L.M.V.-R.); Department of Pathology (R.M.), Center for Molecular Oncology (R.M.), and Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York (R.M.); Division of Surgical Oncology, John Wayne Cancer Institute, Santa Monica, California (D.L.M.); Brain Tumor Center, Saint John's Health Center, Santa Monica, California (G.B., D.F.K.)
| | - Maria Roqué
- Department of Molecular Oncology, John Wayne Cancer Institute, Santa Monica, California (D.M.M., J.L.H., D.S.B.H.); Department of Tissue Oncology and Diagnostic Pathology (R.A.S., M.E.B., J.F.T.) and Department of Melanoma and Surgical Oncology, Royal Prince Alfred Hospital, Sydney, Australia (J.F.T.); Sydney Medical School, The University of Sydney, Sydney, Australia (R.A.S., J.S.W., M.E.B., J.F.T.); Melanoma Institute Australia, Sydney, Australia (R.A.S., J.S.W.); Cellular and Molecular Biology Laboratory, Institute of Histology and Embryology, Mendoza, Argentina (M.R.); Tumor Biology Laboratory, Institute of Medicine and Experimental Biology of Cuyo, Mendoza, Argentina (L.M.V.-R.); Department of Pathology (R.M.), Center for Molecular Oncology (R.M.), and Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York (R.M.); Division of Surgical Oncology, John Wayne Cancer Institute, Santa Monica, California (D.L.M.); Brain Tumor Center, Saint John's Health Center, Santa Monica, California (G.B., D.F.K.)
| | - Laura M Vargas-Roig
- Department of Molecular Oncology, John Wayne Cancer Institute, Santa Monica, California (D.M.M., J.L.H., D.S.B.H.); Department of Tissue Oncology and Diagnostic Pathology (R.A.S., M.E.B., J.F.T.) and Department of Melanoma and Surgical Oncology, Royal Prince Alfred Hospital, Sydney, Australia (J.F.T.); Sydney Medical School, The University of Sydney, Sydney, Australia (R.A.S., J.S.W., M.E.B., J.F.T.); Melanoma Institute Australia, Sydney, Australia (R.A.S., J.S.W.); Cellular and Molecular Biology Laboratory, Institute of Histology and Embryology, Mendoza, Argentina (M.R.); Tumor Biology Laboratory, Institute of Medicine and Experimental Biology of Cuyo, Mendoza, Argentina (L.M.V.-R.); Department of Pathology (R.M.), Center for Molecular Oncology (R.M.), and Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York (R.M.); Division of Surgical Oncology, John Wayne Cancer Institute, Santa Monica, California (D.L.M.); Brain Tumor Center, Saint John's Health Center, Santa Monica, California (G.B., D.F.K.)
| | - Jamie L Huynh
- Department of Molecular Oncology, John Wayne Cancer Institute, Santa Monica, California (D.M.M., J.L.H., D.S.B.H.); Department of Tissue Oncology and Diagnostic Pathology (R.A.S., M.E.B., J.F.T.) and Department of Melanoma and Surgical Oncology, Royal Prince Alfred Hospital, Sydney, Australia (J.F.T.); Sydney Medical School, The University of Sydney, Sydney, Australia (R.A.S., J.S.W., M.E.B., J.F.T.); Melanoma Institute Australia, Sydney, Australia (R.A.S., J.S.W.); Cellular and Molecular Biology Laboratory, Institute of Histology and Embryology, Mendoza, Argentina (M.R.); Tumor Biology Laboratory, Institute of Medicine and Experimental Biology of Cuyo, Mendoza, Argentina (L.M.V.-R.); Department of Pathology (R.M.), Center for Molecular Oncology (R.M.), and Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York (R.M.); Division of Surgical Oncology, John Wayne Cancer Institute, Santa Monica, California (D.L.M.); Brain Tumor Center, Saint John's Health Center, Santa Monica, California (G.B., D.F.K.)
| | - James S Wilmott
- Department of Molecular Oncology, John Wayne Cancer Institute, Santa Monica, California (D.M.M., J.L.H., D.S.B.H.); Department of Tissue Oncology and Diagnostic Pathology (R.A.S., M.E.B., J.F.T.) and Department of Melanoma and Surgical Oncology, Royal Prince Alfred Hospital, Sydney, Australia (J.F.T.); Sydney Medical School, The University of Sydney, Sydney, Australia (R.A.S., J.S.W., M.E.B., J.F.T.); Melanoma Institute Australia, Sydney, Australia (R.A.S., J.S.W.); Cellular and Molecular Biology Laboratory, Institute of Histology and Embryology, Mendoza, Argentina (M.R.); Tumor Biology Laboratory, Institute of Medicine and Experimental Biology of Cuyo, Mendoza, Argentina (L.M.V.-R.); Department of Pathology (R.M.), Center for Molecular Oncology (R.M.), and Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York (R.M.); Division of Surgical Oncology, John Wayne Cancer Institute, Santa Monica, California (D.L.M.); Brain Tumor Center, Saint John's Health Center, Santa Monica, California (G.B., D.F.K.)
| | - Rajmohan Murali
- Department of Molecular Oncology, John Wayne Cancer Institute, Santa Monica, California (D.M.M., J.L.H., D.S.B.H.); Department of Tissue Oncology and Diagnostic Pathology (R.A.S., M.E.B., J.F.T.) and Department of Melanoma and Surgical Oncology, Royal Prince Alfred Hospital, Sydney, Australia (J.F.T.); Sydney Medical School, The University of Sydney, Sydney, Australia (R.A.S., J.S.W., M.E.B., J.F.T.); Melanoma Institute Australia, Sydney, Australia (R.A.S., J.S.W.); Cellular and Molecular Biology Laboratory, Institute of Histology and Embryology, Mendoza, Argentina (M.R.); Tumor Biology Laboratory, Institute of Medicine and Experimental Biology of Cuyo, Mendoza, Argentina (L.M.V.-R.); Department of Pathology (R.M.), Center for Molecular Oncology (R.M.), and Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York (R.M.); Division of Surgical Oncology, John Wayne Cancer Institute, Santa Monica, California (D.L.M.); Brain Tumor Center, Saint John's Health Center, Santa Monica, California (G.B., D.F.K.)
| | - Michael E Buckland
- Department of Molecular Oncology, John Wayne Cancer Institute, Santa Monica, California (D.M.M., J.L.H., D.S.B.H.); Department of Tissue Oncology and Diagnostic Pathology (R.A.S., M.E.B., J.F.T.) and Department of Melanoma and Surgical Oncology, Royal Prince Alfred Hospital, Sydney, Australia (J.F.T.); Sydney Medical School, The University of Sydney, Sydney, Australia (R.A.S., J.S.W., M.E.B., J.F.T.); Melanoma Institute Australia, Sydney, Australia (R.A.S., J.S.W.); Cellular and Molecular Biology Laboratory, Institute of Histology and Embryology, Mendoza, Argentina (M.R.); Tumor Biology Laboratory, Institute of Medicine and Experimental Biology of Cuyo, Mendoza, Argentina (L.M.V.-R.); Department of Pathology (R.M.), Center for Molecular Oncology (R.M.), and Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York (R.M.); Division of Surgical Oncology, John Wayne Cancer Institute, Santa Monica, California (D.L.M.); Brain Tumor Center, Saint John's Health Center, Santa Monica, California (G.B., D.F.K.)
| | - Garni Barkhoudarian
- Department of Molecular Oncology, John Wayne Cancer Institute, Santa Monica, California (D.M.M., J.L.H., D.S.B.H.); Department of Tissue Oncology and Diagnostic Pathology (R.A.S., M.E.B., J.F.T.) and Department of Melanoma and Surgical Oncology, Royal Prince Alfred Hospital, Sydney, Australia (J.F.T.); Sydney Medical School, The University of Sydney, Sydney, Australia (R.A.S., J.S.W., M.E.B., J.F.T.); Melanoma Institute Australia, Sydney, Australia (R.A.S., J.S.W.); Cellular and Molecular Biology Laboratory, Institute of Histology and Embryology, Mendoza, Argentina (M.R.); Tumor Biology Laboratory, Institute of Medicine and Experimental Biology of Cuyo, Mendoza, Argentina (L.M.V.-R.); Department of Pathology (R.M.), Center for Molecular Oncology (R.M.), and Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York (R.M.); Division of Surgical Oncology, John Wayne Cancer Institute, Santa Monica, California (D.L.M.); Brain Tumor Center, Saint John's Health Center, Santa Monica, California (G.B., D.F.K.)
| | - John F Thompson
- Department of Molecular Oncology, John Wayne Cancer Institute, Santa Monica, California (D.M.M., J.L.H., D.S.B.H.); Department of Tissue Oncology and Diagnostic Pathology (R.A.S., M.E.B., J.F.T.) and Department of Melanoma and Surgical Oncology, Royal Prince Alfred Hospital, Sydney, Australia (J.F.T.); Sydney Medical School, The University of Sydney, Sydney, Australia (R.A.S., J.S.W., M.E.B., J.F.T.); Melanoma Institute Australia, Sydney, Australia (R.A.S., J.S.W.); Cellular and Molecular Biology Laboratory, Institute of Histology and Embryology, Mendoza, Argentina (M.R.); Tumor Biology Laboratory, Institute of Medicine and Experimental Biology of Cuyo, Mendoza, Argentina (L.M.V.-R.); Department of Pathology (R.M.), Center for Molecular Oncology (R.M.), and Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York (R.M.); Division of Surgical Oncology, John Wayne Cancer Institute, Santa Monica, California (D.L.M.); Brain Tumor Center, Saint John's Health Center, Santa Monica, California (G.B., D.F.K.)
| | - Donald L Morton
- Department of Molecular Oncology, John Wayne Cancer Institute, Santa Monica, California (D.M.M., J.L.H., D.S.B.H.); Department of Tissue Oncology and Diagnostic Pathology (R.A.S., M.E.B., J.F.T.) and Department of Melanoma and Surgical Oncology, Royal Prince Alfred Hospital, Sydney, Australia (J.F.T.); Sydney Medical School, The University of Sydney, Sydney, Australia (R.A.S., J.S.W., M.E.B., J.F.T.); Melanoma Institute Australia, Sydney, Australia (R.A.S., J.S.W.); Cellular and Molecular Biology Laboratory, Institute of Histology and Embryology, Mendoza, Argentina (M.R.); Tumor Biology Laboratory, Institute of Medicine and Experimental Biology of Cuyo, Mendoza, Argentina (L.M.V.-R.); Department of Pathology (R.M.), Center for Molecular Oncology (R.M.), and Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York (R.M.); Division of Surgical Oncology, John Wayne Cancer Institute, Santa Monica, California (D.L.M.); Brain Tumor Center, Saint John's Health Center, Santa Monica, California (G.B., D.F.K.)
| | - Daniel F Kelly
- Department of Molecular Oncology, John Wayne Cancer Institute, Santa Monica, California (D.M.M., J.L.H., D.S.B.H.); Department of Tissue Oncology and Diagnostic Pathology (R.A.S., M.E.B., J.F.T.) and Department of Melanoma and Surgical Oncology, Royal Prince Alfred Hospital, Sydney, Australia (J.F.T.); Sydney Medical School, The University of Sydney, Sydney, Australia (R.A.S., J.S.W., M.E.B., J.F.T.); Melanoma Institute Australia, Sydney, Australia (R.A.S., J.S.W.); Cellular and Molecular Biology Laboratory, Institute of Histology and Embryology, Mendoza, Argentina (M.R.); Tumor Biology Laboratory, Institute of Medicine and Experimental Biology of Cuyo, Mendoza, Argentina (L.M.V.-R.); Department of Pathology (R.M.), Center for Molecular Oncology (R.M.), and Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York (R.M.); Division of Surgical Oncology, John Wayne Cancer Institute, Santa Monica, California (D.L.M.); Brain Tumor Center, Saint John's Health Center, Santa Monica, California (G.B., D.F.K.)
| | - Dave S B Hoon
- Department of Molecular Oncology, John Wayne Cancer Institute, Santa Monica, California (D.M.M., J.L.H., D.S.B.H.); Department of Tissue Oncology and Diagnostic Pathology (R.A.S., M.E.B., J.F.T.) and Department of Melanoma and Surgical Oncology, Royal Prince Alfred Hospital, Sydney, Australia (J.F.T.); Sydney Medical School, The University of Sydney, Sydney, Australia (R.A.S., J.S.W., M.E.B., J.F.T.); Melanoma Institute Australia, Sydney, Australia (R.A.S., J.S.W.); Cellular and Molecular Biology Laboratory, Institute of Histology and Embryology, Mendoza, Argentina (M.R.); Tumor Biology Laboratory, Institute of Medicine and Experimental Biology of Cuyo, Mendoza, Argentina (L.M.V.-R.); Department of Pathology (R.M.), Center for Molecular Oncology (R.M.), and Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York (R.M.); Division of Surgical Oncology, John Wayne Cancer Institute, Santa Monica, California (D.L.M.); Brain Tumor Center, Saint John's Health Center, Santa Monica, California (G.B., D.F.K.)
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Zhang A, Gao C, Han X, Wang L, Yu C, Zeng X, Chen L, Li D, Chen W. Inactivation of p15 INK4b in chronic arsenic poisoning cases. Toxicol Rep 2014; 1:692-698. [PMID: 28962283 PMCID: PMC5598098 DOI: 10.1016/j.toxrep.2014.08.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2014] [Revised: 07/30/2014] [Accepted: 08/13/2014] [Indexed: 11/27/2022] Open
Abstract
Arsenic exposure from burning high arsenic-containing coal has been associated with human skin lesion and cancer. However, the mechanisms of arsenic-related carcinogenesis are not fully understood. Inactivation of critical tumor suppression genes by epigenetic regulation or genetic modification might contribute to arsenic-induced carcinogenicity. This study aims to clarify the correlation between arsenic pollution and functional defect of p15INK4b gene in arsenic exposure residents from a region of Guizhou Province, China. To this end, 103 arsenic exposure residents and 105 control subjects were recruited in this study. The results showed that the exposure group exhibited higher levels of urinary and hair arsenic compared with the control group (55.28 vs 28.87 μg/L, 5.16 vs 1.36 μg/g). Subjects with higher arsenic concentrations are more likely to have p15INK4b methylation and gene deletion (χ2 = 4.28, P = 0.04 and χ2 = 4.31, P = 0.04). We also found that the degree of p15INK4b hypermethylation and gene deletion occurred at higher incidence in the poisoning cases with skin cancer (3.7% and 14.81% in non-skin cancer group, 41.18% and 47.06 in skin cancer group), and were significantly associated with the stage of skin lesions (χ2 = 12.82, P < 0.01 and χ2 = 7.835, P = 0.005). These observations indicate that inactivation of p15INK4b through genetic alteration or epigenetic modification is a common event that is associated with arsenic exposure and the development of arsenicosis.
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Affiliation(s)
- Aihua Zhang
- Department of Toxicology, School of Public Health, Guiyang Medical University, Guiyang 550004, China
| | - Chen Gao
- Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
| | - Xue Han
- Department of Toxicology, School of Public Health, Guiyang Medical University, Guiyang 550004, China
| | - Lifang Wang
- Department of Toxicology, School of Public Health, Guiyang Medical University, Guiyang 550004, China
| | - Chun Yu
- Department of Toxicology, School of Public Health, Guiyang Medical University, Guiyang 550004, China
| | - Xiaowen Zeng
- Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
| | - Liping Chen
- Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
| | - Daochuan Li
- Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
| | - Wen Chen
- Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
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17
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Xue L, Ouyang Q, Li J, Meng X, Li Y, Xing L, Wang J, Yan X, Zhang X. Different roles for p16(INK) (4a) -Rb pathway and INK4a/ARF methylation between adenocarcinomas of gastric cardia and distal stomach. J Gastroenterol Hepatol 2014; 29:1418-26. [PMID: 25123601 DOI: 10.1111/jgh.12547] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/13/2014] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND AIM The incidence of distal gastric adenocarcinoma has significantly decreased, but gastric cardia adenocarcinoma has been on the rise. Cardia adenocarcinoma might be a specific entity distinct from the carcinoma of the rest stomach. The aim was to explore putative differences in p16(INK) (4a) -retinoblastoma (Rb) pathway and INK4a/ARF methylation between gastric cardia and distal adenocarcinomas. METHODS Ninety-six cardia adenocarcinomas and 79 distal samples were analyzed for comparing p16(INK) (4a) -Rb expressions, INK4a/ARF deletion, and methylation using immunohistochemistry, polymerase chain reaction, and methylation-specific polymerase chain reaction. RESULTS The expression of p16(INK) (4a) in cardia adenocarcinoma (43.2%) was significantly lower than in distal cases (75.0%, P < 0.05). As well, cardia adenocarcinoma showed lower expression of p14(ARF) compared with distal cases (34.1% vs 57.5%, P < 0.05). The incidence of p16(INK) (4a) deletion was 20.5% and 15.0%, while p14(ARF) deletion was 18.2% and 10.0% in cardia and distal adenocarcinomas, respectively, showing no significant differences between two entities. However, the incidences of p14(ARF) and p16(INK) (4a) methylation in cardia adenocarcinoma were significantly higher than in distal samples (p14(ARF) : 61.5% vs 43.6%; p16(INK) (4a) : 73.1% vs 51.3%, P < 0.05). INK4a/ARF methylations were more prevalent in poorly differentiated cardia carcinoma compared with poorly differentiated distal cases. CONCLUSIONS There were differences in p16(INK) (4a) -Rb immunotypes and INK4a/ARF methylation between two entities, indicating that cardia adenocarcinoma may be different in cell proliferation, differentiation, and gene biomarkers compared with distal gastric adenocarcinoma.
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Affiliation(s)
- Liying Xue
- Department of Pathology, Hebei Medical University, Shijiazhuang, China
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18
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Molecular pathology of malignant melanoma: changing the clinical practice paradigm toward a personalized approach. Hum Pathol 2014; 45:1315-26. [PMID: 24856851 DOI: 10.1016/j.humpath.2014.04.001] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2014] [Revised: 04/04/2014] [Accepted: 04/09/2014] [Indexed: 12/14/2022]
Abstract
Melanocytic proliferations are notoriously difficult lesions to evaluate histologically, even among experts, as there is a lack of objective, highly reproducible criteria, which can be broadly applied to the wide range of melanocytic lesions encountered in daily practice. These difficult diagnoses are undeniably further compounded by the substantial medicolegal risks of an "erroneous" diagnosis. Molecular information and classification of melanocytic lesions is already vast and constantly expanding. The application of molecular techniques for the diagnosis of benignity or malignancy is, at times, confusing and limits its utility if not used properly. In addition, current and future therapies will necessitate molecular classification of melanoma into one of several distinct subtypes for appropriate patient-specific therapy. An understanding of what different molecular markers can and cannot predict is of the utmost importance. We discuss both mutational analysis and chromosomal gains/losses to help clarify this continually developing and confusing facet of pathology.
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19
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Lopez-Bergami P. The role of mitogen- and stress-activated protein kinase pathways in melanoma. Pigment Cell Melanoma Res 2014; 24:902-21. [PMID: 21914141 DOI: 10.1111/j.1755-148x.2011.00908.x] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Recent discoveries have increased our comprehension of the molecular signaling events critical for melanoma development and progression. Many oncogenes driving melanoma have been identified, and most of them exert their oncogenic effects through the activation of the RAF/MEK/ERK mitogen-activated protein kinase (MAPK) pathway. The c-Jun N-terminal kinase (JNK) and p38 MAPK pathways are also important in melanoma, but their precise role is not clear yet. This review summarizes our current knowledge on the role of the three main MAPK pathways, extracellular regulated kinase (ERK), JNK, and p38, and their impact on melanoma biology. Although the results obtained with BRAF inhibitors in melanoma patients are impressive, several mechanisms of acquired resistance have emerged. To overcome this obstacle constitutes the new challenge in melanoma therapy. Given the major role that MAPKs play in melanoma, understanding their functions and the interconnection among them and with other signaling pathways represents a step forward toward this goal.
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Affiliation(s)
- Pablo Lopez-Bergami
- Instituto de Medicina y Biología Experimental, CONICET, Buenos Aires, Argentina.
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20
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Pos Z, Spivey TL, Liu H, Sommariva M, Chen J, Wunderlich JR, Parisi G, Tomei S, Ayotte BD, Stroncek DF, Malek JA, Robbins PF, Rivoltini L, Maio M, Chouchane L, Wang E, Marincola FM. Longitudinal study of recurrent metastatic melanoma cell lines underscores the individuality of cancer biology. J Invest Dermatol 2013; 134:1389-1396. [PMID: 24270663 PMCID: PMC3989423 DOI: 10.1038/jid.2013.495] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2013] [Revised: 09/22/2013] [Accepted: 10/21/2013] [Indexed: 01/15/2023]
Abstract
Recurrent metastatic melanoma provides a unique opportunity to analyze disease evolution in metastatic cancer. Here, we followed up eight patients with an unusually prolonged history of metastatic melanoma, who developed a total of 26 recurrences over several years. Cell lines derived from each metastasis were analyzed by comparative genomic hybridization and global transcript analysis. We observed that conserved, patient-specific characteristics remain stable in recurrent metastatic melanoma even after years and several recurrences. Differences among individual patients exceeded within-patient lesion variability, both at the DNA copy number (P<0.001) and RNA gene expression level (P<0.001). Conserved patient-specific traits included expression of several cancer/testis antigens and the c-kit proto-oncogene throughout multiple recurrences. Interestingly, subsequent recurrences of different patients did not display consistent or convergent changes toward a more aggressive disease phenotype. Finally, sequential recurrences of the same patient did not descend progressively from each other, as irreversible mutations such as homozygous deletions were frequently not inherited from previous metastases. This study suggests that the late evolution of metastatic melanoma, which markedly turns an indolent disease into a lethal phase, is prone to preserve case-specific traits over multiple recurrences and occurs through a series of random events that do not follow a consistent stepwise process.
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Affiliation(s)
- Zoltan Pos
- Infectious Disease and Immunogenetics Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA; Hungarian Academy of Sciences-Semmelweis University "Lendület" Experimental and Translational Immunomics Research Group, Budapest, Hungary; Department of Genetics, Cell, and Immunobiology, Semmelweis University, Budapest, Hungary
| | - Tara L Spivey
- Infectious Disease and Immunogenetics Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA; Clinical Research Training Program (CRTP), National Institutes of Health, Bethesda, Maryland, USA; Department of General Surgery, Rush University Medical Center, Chicago, Illinois, USA
| | - Hui Liu
- Infectious Disease and Immunogenetics Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA
| | - Michele Sommariva
- Infectious Disease and Immunogenetics Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA; Department of Biomedical Sciences for Health, Universita' degli Studi di Milano, Milan, Italy
| | - Jinguo Chen
- Infectious Disease and Immunogenetics Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA
| | - John R Wunderlich
- Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Giulia Parisi
- Cancer Bioimmunotherapy Unit, Centro di Riferimento Oncologico, Aviano, Italy
| | - Sara Tomei
- Department of Genetic Medicine, Weill Cornell Medical College in Qatar, Education City, Doha, Qatar
| | - Ben D Ayotte
- Department of Biology, Northern Michigan University, Marquette, Michigan, USA
| | - David F Stroncek
- Cell Processing Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA
| | - Joel A Malek
- Department of Genetic Medicine, Weill Cornell Medical College in Qatar, Education City, Doha, Qatar
| | - Paul F Robbins
- Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Licia Rivoltini
- Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Michele Maio
- Cancer Bioimmunotherapy Unit, Centro di Riferimento Oncologico, Aviano, Italy
| | - Lotfi Chouchane
- Weill Cornell Medical College in Qatar, Education City, Doha, Qatar
| | - Ena Wang
- Infectious Disease and Immunogenetics Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA
| | - Francesco M Marincola
- Infectious Disease and Immunogenetics Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA; Research Branch, Sidra Medical and Research Centre, Doha, Qatar.
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21
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Campagne C, Reyes-Gomez E, Battistella M, Bernex F, Château-Joubert S, Huet H, Beermann F, Aubin-Houzelstein G, Egidy G. Histopathological atlas and proposed classification for melanocytic lesions in Tyr::NRas(Q61K) ; Cdkn2a(-/-) transgenic mice. Pigment Cell Melanoma Res 2013; 26:735-42. [PMID: 23647911 DOI: 10.1111/pcmr.12115] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Affiliation(s)
- Cécile Campagne
- UMR955 de Génétique fonctionnelle et médicale, Ecole Nationale Vétérinaire d'Alfort, INRA, Maisons-Alfort, France
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22
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Yasaei H, Gilham E, Pickles JC, Roberts TP, O'Donovan M, Newbold RF. Carcinogen-specific mutational and epigenetic alterations in INK4A, INK4B and p53 tumour-suppressor genes drive induced senescence bypass in normal diploid mammalian cells. Oncogene 2012; 32:171-9. [DOI: 10.1038/onc.2012.45] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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23
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Mimeault M, Batra SK. Novel biomarkers and therapeutic targets for optimizing the therapeutic management of melanomas. World J Clin Oncol 2012; 3:32-42. [PMID: 22442756 PMCID: PMC3309891 DOI: 10.5306/wjco.v3.i3.32] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2011] [Revised: 02/12/2012] [Accepted: 03/05/2012] [Indexed: 02/06/2023] Open
Abstract
Cutaneous malignant melanoma is the most aggressive form of skin cancer with an extremely poor survival rate for the patients diagnosed with locally invasive and metastatic disease states. Intensive research has led in last few years to an improvement of the early detection and curative treatment of primary cutaneous melanomas that are confined to the skin by tumor surgical resection. However, locally advanced and disseminated melanomas are generally resistant to conventional treatments, including ionizing radiation, systemic chemotherapy, immunotherapy and/or adjuvant stem cell-based therapies, and result in the death of patients. The rapid progression of primary melanomas to locally invasive and/or metastatic disease states remains a major obstacle for an early effective diagnosis and a curative therapeutic intervention for melanoma patients. Importantly, recent advances in the melanoma research have led to the identification of different gene products that are often implicated in the malignant transformation of melanocytic cells into melanoma cells, including melanoma stem/progenitor cells, during melanoma initiation and progression to locally advanced and metastatic disease states. The frequent deregulated genes products encompass the oncogenic B-RafV600E and N-RasQ61R mutants, different receptor tyrosine kinases and developmental pathways such as epidermal growth factor receptor (EGFR), stem cell-like factor (SCF) receptor KIT, hedgehog, Wnt/β-catenin, Notch, stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor-4 (CXCR4) and vascular endothelial growth factor (VEGF)/VEGFR receptor. These growth factors can cooperate to activate distinct tumorigenic downstream signaling elements and epithelial-mesenchymal transition (EMT)-associated molecules, including phosphatidylinositol 3’-kinase (PI3K)/Akt/ molecular target of rapamycin (mTOR), nuclear factor-kappaB (NF-κB), macrophage inhibitory cytokine-1 (MIC-1), vimentin, snail and twist. Of therapeutic relevance, these deregulated signal transduction components constitute new potential biomarkers and therapeutic targets of great clinical interest for improving the efficacy of current diagnostic and prognostic methods and management of patients diagnosed with locally advanced, metastatic and/or relapsed melanomas.
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Affiliation(s)
- Murielle Mimeault
- Murielle Mimeault, Surinder K Batra, Department of Biochemistry and Molecular Biology, College of Medicine, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198-5870, United States
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25
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Omholt K, Grafström E, Kanter-Lewensohn L, Hansson J, Ragnarsson-Olding BK. KIT Pathway Alterations in Mucosal Melanomas of the Vulva and Other Sites. Clin Cancer Res 2011; 17:3933-42. [DOI: 10.1158/1078-0432.ccr-10-2917] [Citation(s) in RCA: 127] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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26
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High frequency of p16(INK4A) promoter methylation in NRAS-mutated cutaneous melanoma. J Invest Dermatol 2010; 130:2809-17. [PMID: 20703244 DOI: 10.1038/jid.2010.216] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
The p16(INK4A) tumor suppressor is often deleted, or otherwise inactivated, in malignant melanoma. To investigate the loss of p16(INK4A) in greater detail, we analyzed 77 cutaneous melanoma metastases. Of these 56 retained at least one p16(INK4A) allele, and 21 had biallelic deletions. Using methylation-specific PCR, direct sequencing, and immunohistochemical methods, we analyzed p16(INK4A) promoter methylation, mutations, and protein expression, respectively. In addition, 14 corresponding primary tumors were analyzed for protein expression. Results were compared to clinicopathological parameters and previously obtained data regarding mutations in proto-oncogenes NRAS and BRAF. Results revealed that p16(INK4A) promoter methylation was present in 15 of 59 (25%) metastases; nonsynonymous mutations in 9 of 56 (16%) metastases; and protein expression in 12 of 67 (18%) metastases. Protein expression was lost during progression from primary to metastatic tumors, 71% (10 of 14) and 43% (6 of 14) being positive, respectively. However, the genetic and epigenetic alterations of p16(INK4A) observed could not explain the lack of p16(INK4A) protein in 27 metastases, indicating the presence of additional inactivating mechanisms for p16(INK4A). Interestingly, p16(INK4A) promoter methylation was significantly overrepresented in NRAS-mutated samples compared to NRAS wild-type samples (P=0.0004), indicating an association between these two events.
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27
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Monahan KB, Rozenberg GI, Krishnamurthy J, Johnson SM, Liu W, Bradford MK, Horner J, Depinho RA, Sharpless NE. Somatic p16(INK4a) loss accelerates melanomagenesis. Oncogene 2010; 29:5809-17. [PMID: 20697345 PMCID: PMC3007178 DOI: 10.1038/onc.2010.314] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Loss of p16INK4a–RB and ARF–p53 tumor suppressor pathways, as well as activation of RAS–RAF signaling, is seen in a majority of human melanomas. Although heterozygous germline mutations of p16INK4a are associated with familial melanoma, most melanomas result from somatic genetic events: often p16INK4a loss and N-RAS or B-RAF mutational activation, with a minority possessing alternative genetic alterations such as activating mutations in K-RAS and/or p53 inactivation. To generate a murine model of melanoma featuring some of these somatic genetic events, we engineered a novel conditional p16INK4a-null allele and combined this allele with a melanocyte-specific, inducible CRE recombinase strain, a conditional p53-null allele and a loxP-stop-loxP activatable oncogenic K-Ras allele. We found potent synergy between melanocyte-specific activation of K-Ras and loss of p16INK4a and/or p53 in melanomagenesis. Mice harboring melanocyte-specific activated K-Ras and loss of p16INK4a and/or p53 developed invasive, unpigmented and nonmetastatic melanomas with short latency and high penetrance. In addition, the capacity of these somatic genetic events to rapidly induce melanomas in adult mice suggests that melanocytes remain susceptible to transformation throughout adulthood.
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Affiliation(s)
- K B Monahan
- Departments of Medicine and Genetics, The Lineberger Comprehensive Cancer Center, The Center for Environmental Health and Susceptibility, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7295, USA
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28
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Ivanov SV, Goparaju CMV, Lopez P, Zavadil J, Toren-Haritan G, Rosenwald S, Hoshen M, Chajut A, Cohen D, Pass HI. Pro-tumorigenic effects of miR-31 loss in mesothelioma. J Biol Chem 2010; 285:22809-17. [PMID: 20463022 PMCID: PMC2906272 DOI: 10.1074/jbc.m110.100354] [Citation(s) in RCA: 103] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2010] [Revised: 04/12/2010] [Indexed: 11/06/2022] Open
Abstract
The human genome encodes several hundred microRNA (miRNA) genes that produce small (21-23n) single strand regulatory RNA molecules. Although abnormal expression of miRNAs has been linked to cancer progression, the mechanisms of this dysregulation are poorly understood. Malignant mesothelioma (MM) of pleura is an aggressive and highly lethal cancer resistant to conventional therapies. We and others previously linked loss of the 9p21.3 chromosome in MM with short time to tumor recurrence. In this study, we report that MM cell lines derived from patients with more aggressive disease fail to express miR-31, a microRNA recently linked with suppression of breast cancer metastases. We further demonstrate that this loss is due to homozygous deletion of the miR-31-encoding gene that resides in 9p21.3. Functional assessment of miR-31 activity revealed its ability to inhibit proliferation, migration, invasion, and clonogenicity of MM cells. Re-introduction of miR-31 suppressed the cell cycle and inhibited expression of multiple factors involved in cooperative maintenance of DNA replication and cell cycle progression, including pro-survival phosphatase PPP6C, which was previously associated with chemotherapy and radiation therapy resistance, and maintenance of chromosomal stability. PPP6C, whose mRNA is distinguished with three miR-31-binding sites in its 3'-untranslated region, was consistently down-regulated by miR-31 introduction and up-regulated in clinical MM specimens as compared with matched normal tissues. Taken together, our data suggest that tumor-suppressive propensity of miR-31 can be used for development of new therapies against mesothelioma and other cancers that show loss of the 9p21.3 chromosome.
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Affiliation(s)
- Sergey V Ivanov
- Department of Otolaryngology, Vanderbilt School of Medicine, Nashville, Tennessee 37232, USA.
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Gaddameedhi S, Kemp MG, Reardon JT, Shields JM, Smith-Roe SL, Kaufmann WK, Sancar A. Similar nucleotide excision repair capacity in melanocytes and melanoma cells. Cancer Res 2010; 70:4922-30. [PMID: 20501836 PMCID: PMC2891231 DOI: 10.1158/0008-5472.can-10-0095] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Sunlight UV exposure produces DNA photoproducts in skin that are repaired solely by nucleotide excision repair in humans. A significant fraction of melanomas are thought to result from UV-induced DNA damage that escapes repair; however, little evidence is available about the functional capacity of normal human melanocytes, malignant melanoma cells, and metastatic melanoma cells to repair UV-induced photoproducts in DNA. In this study, we measured nucleotide excision repair in both normal melanocytes and a panel of melanoma cell lines. Our results show that in 11 of 12 melanoma cell lines tested, UV photoproduct repair occurred as efficiently as in primary melanocytes. Importantly, repair capacity was not affected by mutation in the N-RAS or B-RAF oncogenes, nor was a difference observed between a highly metastatic melanoma cell line (A375SM) or its parental line (A375P). Lastly, we found that although p53 status contributed to photoproduct removal efficiency, its role did not seem to be mediated by enhanced expression or activity of DNA binding protein DDB2. We concluded that melanoma cells retain capacity for nucleotide excision repair, the loss of which probably does not commonly contribute to melanoma progression.
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Affiliation(s)
- Shobhan Gaddameedhi
- Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, NC, USA
- Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC, USA
| | - Michael G. Kemp
- Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, NC, USA
- Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC, USA
| | - Joyce T. Reardon
- Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, NC, USA
- Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC, USA
| | - Janiel M. Shields
- Department of Radiation Oncology, University of North Carolina School of Medicine, Chapel Hill, NC, USA
- Department of Dermatology, University of North Carolina School of Medicine, Chapel Hill, NC, USA
| | - Stephanie L. Smith-Roe
- Department of Pathology and Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, USA
| | - William K. Kaufmann
- Department of Pathology and Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, USA
- Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC, USA
- Center for Environmental Health and Susceptibility, University of North Carolina School of Medicine, Chapel Hill, NC, USA
| | - Aziz Sancar
- Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, NC, USA
- Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC, USA
- Center for Environmental Health and Susceptibility, University of North Carolina School of Medicine, Chapel Hill, NC, USA
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30
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Busch C, Geisler J, Knappskog S, Lillehaug JR, Lønning PE. Alterations in the p53 pathway and p16INK4a expression predict overall survival in metastatic melanoma patients treated with dacarbazine. J Invest Dermatol 2010; 130:2514-6. [PMID: 20505745 DOI: 10.1038/jid.2010.138] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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31
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Conway C, Beswick S, Elliott F, Chang YM, Randerson-Moor J, Harland M, Affleck P, Marsden J, Sanders DS, Boon A, Knowles MA, Bishop DT, Newton-Bishop JA. Deletion at chromosome arm 9p in relation to BRAF/NRAS mutations and prognostic significance for primary melanoma. Genes Chromosomes Cancer 2010; 49:425-38. [PMID: 20140953 PMCID: PMC2948432 DOI: 10.1002/gcc.20753] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2009] [Accepted: 12/22/2009] [Indexed: 11/05/2022] Open
Abstract
We report an investigation of gene dosage at 9p21.3 and mutations in BRAF and NRAS, as predictors of relapse and histological markers of poor melanoma prognosis. Formalin-fixed primary melanomas from 74 relapsed and 42 nonrelapsed patients were sequenced for common BRAF and NRAS mutations (N = 71 results) and gene dosage at 9p21.3 including the genes CDKN2A (which encodes CDKN2A and P14ARF), CDKN2B (CDKN2B), and MTAP was measured using multiplexed ligation-dependant probe amplification (MLPA), (N = 75 results). BRAF/NRAS mutations were detected in 77% of relapsers and 58% of nonrelapsers (Fisher's exact P = 0.17), and did not predict ulceration or mitotic rate. There was no relationship between BRAF/NRAS mutations and gene dosage at 9p21.3. Reduced gene dosage at MTAP showed a borderline association with BRAF mutation (P = 0.04) and reduced gene dosage at the interferon gene cluster was borderline associated with wild type NRAS (P = 0.05). Reduced gene dosage in the CDKN2A regions coding for CDKN2A was associated with an increased risk of relapse (P = 0.03). Reduced gene dosage across 9p21.3 was associated with increased tumor thickness, mitotic rate, and ulceration (P = 0.02, 0.02, and 0.002, respectively), specifically in coding regions impacting on CDKN2B and P14ARF and CDKN2A. Loss at MTAP (P = 0.05) and the interferon gene cluster (P = 0.03) on 9p21 was also associated with tumor ulceration. There was no association between reduced gene dosage at 9p21.3 and subtype or site of tumor. This study presents supportive evidence that CDKN2B, P14ARF, and CDKN2A may all play a tumor suppressor role in melanoma progression.
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Affiliation(s)
- Caroline Conway
- Section of Epidemiology and Biostatistics, Leeds Institute of Molecular Medicine, University of Leeds, St. James's University HospitalLeeds, UK
| | - Samantha Beswick
- Section of Epidemiology and Biostatistics, Leeds Institute of Molecular Medicine, University of Leeds, St. James's University HospitalLeeds, UK
| | - Faye Elliott
- Section of Epidemiology and Biostatistics, Leeds Institute of Molecular Medicine, University of Leeds, St. James's University HospitalLeeds, UK
| | - Yu-Mei Chang
- Section of Epidemiology and Biostatistics, Leeds Institute of Molecular Medicine, University of Leeds, St. James's University HospitalLeeds, UK
| | - Juliette Randerson-Moor
- Section of Epidemiology and Biostatistics, Leeds Institute of Molecular Medicine, University of Leeds, St. James's University HospitalLeeds, UK
| | - Mark Harland
- Section of Epidemiology and Biostatistics, Leeds Institute of Molecular Medicine, University of Leeds, St. James's University HospitalLeeds, UK
| | - Paul Affleck
- Section of Epidemiology and Biostatistics, Leeds Institute of Molecular Medicine, University of Leeds, St. James's University HospitalLeeds, UK
| | - Jerry Marsden
- Department of Dermatology, University Hospital Birmingham NHS Foundation TrustUK
| | - D Scott Sanders
- Department of Histopathology, Coventry and Warwickshire PathologyLakin Road, Warwick, UK
| | - Andy Boon
- Department of Histopathology, Leeds Teaching Hospitals NHS Trust, St. James's University HospitalLeeds, UK
| | - Margaret A Knowles
- Section of Experimental Oncology, Leeds Institute of Molecular Medicine, University of Leeds, St. James's University HospitalLeeds, UK
| | - D Timothy Bishop
- Section of Epidemiology and Biostatistics, Leeds Institute of Molecular Medicine, University of Leeds, St. James's University HospitalLeeds, UK
| | - Julia A Newton-Bishop
- Section of Epidemiology and Biostatistics, Leeds Institute of Molecular Medicine, University of Leeds, St. James's University HospitalLeeds, UK
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32
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Casula M, Budroni M, Cossu A, Ascierto PA, Mozzillo N, Canzanella S, Muggiano A, Palmieri G. The susceptibility CDKN2 locus may have a role on prognosis of melanoma patients. Ann Oncol 2010; 21:1379-1380. [PMID: 20231302 DOI: 10.1093/annonc/mdq056] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Affiliation(s)
- M Casula
- Institute of Biomolecular Chemistry, National Research Council, Sassari
| | - M Budroni
- Department of Epidemiology, Local Health Unit 1, Sassari
| | - A Cossu
- Department of Pathology, Hospital-University Health Unit, Sassari
| | - P A Ascierto
- Melanoma Unit, National Cancer Institute-Fondazione Pascale, Naples
| | - N Mozzillo
- Melanoma Unit, National Cancer Institute-Fondazione Pascale, Naples
| | - S Canzanella
- House Hospital Onlus Nonprofit Organization, Naples
| | - A Muggiano
- Medical Oncology, Regional Cancer Hospital-Businco, Cagliari, Italy
| | - G Palmieri
- Institute of Biomolecular Chemistry, National Research Council, Sassari.
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33
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Mimeault M, Batra SK. Recent advances on skin-resident stem/progenitor cell functions in skin regeneration, aging and cancers and novel anti-aging and cancer therapies. J Cell Mol Med 2009; 14:116-34. [PMID: 19725922 PMCID: PMC2916233 DOI: 10.1111/j.1582-4934.2009.00885.x] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Recent advances in skin-resident adult stem/progenitor cell research have revealed that these immature and regenerative cells with a high longevity provide critical functions in maintaining skin homeostasis and repair after severe injuries along the lifespan of individuals. The establishment of the functional properties of distinct adult stem/progenitor cells found in skin epidermis and hair follicles and extrinsic signals from their niches, which are deregulated during their aging and malignant transformation, has significantly improved our understanding on the etiopathogenesis of diverse human skin disorders and cancers. Particularly, enhanced ultraviolet radiation exposure, inflammation and oxidative stress and telomere attrition during chronological aging may induce severe DNA damages and genomic instability in the skin-resident stem/progenitor cells and their progenies. These molecular events may result in the alterations in key signalling components controlling their self-renewal and/or regenerative capacities as well as the activation of tumour suppressor gene products that trigger their growth arrest and senescence or apoptotic death. The progressive decline in the regenerative functions and/or number of skin-resident adult stem/progenitor cells may cause diverse skin diseases with advancing age. Moreover, the photoaging, telomerase re-activation and occurrence of different oncogenic events in skin-resident adult stem/progenitor cells may also culminate in their malignant transformation into cancer stem/progenitor cells and skin cancer initiation and progression. Therefore, the anti-inflammatory and anti-oxidant treatments and stem cell-replacement and gene therapies as well as the molecular targeting of their malignant counterpart, skin cancer-initiating cells offer great promise to treat diverse skin disorders and cancers.
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Affiliation(s)
- Murielle Mimeault
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA.
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34
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Kiwerska K, Rydzanicz M, Kram A, Pastok M, Antkowiak A, Domagała W, Szyfter K. Mutational analysis of CDKN2A gene in a group of 390 larynx cancer patients. Mol Biol Rep 2009; 37:325-32. [DOI: 10.1007/s11033-009-9731-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2009] [Accepted: 08/04/2009] [Indexed: 01/30/2023]
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35
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Hilliard NJ, Krahl D, Sellheyer K. p16 Expression differentiates between desmoplastic Spitz nevus and desmoplastic melanoma. J Cutan Pathol 2009; 36:753-9. [DOI: 10.1111/j.1600-0560.2008.01154.x] [Citation(s) in RCA: 79] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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36
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Freedberg DE, Rigas SH, Russak J, Gai W, Kaplow M, Osman I, Turner F, Randerson-Moor JA, Houghton A, Busam K, Timothy Bishop D, Bastian BC, Newton-Bishop JA, Polsky D. Frequent p16-independent inactivation of p14ARF in human melanoma. J Natl Cancer Inst 2008; 100:784-95. [PMID: 18505964 DOI: 10.1093/jnci/djn157] [Citation(s) in RCA: 80] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND The tumor suppressors p14(ARF) (ARF) and p16(INK4A) (p16) are encoded by overlapping reading frames at the CDKN2A/INK4A locus on chromosome 9p21. In human melanoma, the accumulated evidence has suggested that the predominant tumor suppressor at 9p21 is p16, not ARF. However, recent observations from melanoma-prone families and murine melanoma models suggest a p16-independent tumor suppressor role for ARF. We analyzed a group of melanoma metastases and cell lines to investigate directly whether somatic alterations to the ARF gene support its role as a p16-independent tumor suppressor in human melanoma, assuming that two alterations (genetic and/or epigenetic) would be required to inactivate a gene. METHODS We examined the p16/ARF locus in 60 melanoma metastases from 58 patients and in 9 human melanoma cell lines using multiplex ligation-dependent probe amplification and multiplex polymerase chain reaction (PCR) to detect deletions, methylation-specific PCR to detect promoter methylation, direct sequencing to detect mutations affecting ARF and p16, and, in a subset of 20 tumors, immunohistochemistry to determine the effect of these alterations on p16 protein expression. All statistical tests were two-sided. RESULTS We observed two or more alterations to the ARF gene in 26/60 (43%) metastases. The p16 gene sustained two or more alterations in 13/60 (22%) metastases (P = .03). Inactivation of ARF in the presence of wild-type p16 was seen in 18/60 (30%) metastases. CONCLUSION Genetic and epigenetic analyses of the human 9p21 locus indicate that modifications of ARF occur independently of p16 inactivation in human melanoma and suggest that ARF is more frequently inactivated than p16.
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Affiliation(s)
- Daniel E Freedberg
- Department of Dermatology, New York University School of Medicine, 550 First Ave, New York, NY 10016, USA
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37
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Abstract
Understanding regulatory pathways involved in melanoma development and progression has advanced significantly in recent years. It is now appreciated that melanoma is the result of complex changes in multiple signaling pathways that affect growth control, metabolism, motility and the ability to escape cell death programs. Here we review the major signaling pathways currently known to be deregulated in melanoma with an implication to its development and progression. Among these pathways are Ras, B-Raf, MEK, PTEN, phosphatidylinositol-3 kinase (PI3Ks) and Akt which are constitutively activated in a significant number of melanoma tumors, in most cases due to genomic change. Other pathways discussed in this review include the [Janus kinase/signal transducer and activator of transcription (JAK/STAT), transforming growth factor-beta pathways which are also activated in melanoma, although the underlying mechanism is not yet clear. As a paradigm for remodeled signaling pathways, melanoma also offers a unique opportunity for targeted drug development.
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Affiliation(s)
- Pablo Lopez-Bergami
- Signal Transduction Program, Burnham Institute for Medical Research, La Jolla, CA
| | - Boris Fitchman
- Signal Transduction Program, Burnham Institute for Medical Research, La Jolla, CA
| | - Ze’ev Ronai
- Signal Transduction Program, Burnham Institute for Medical Research, La Jolla, CA
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38
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Kaufmann WK, Nevis KR, Qu P, Ibrahim JG, Zhou T, Zhou Y, Simpson DA, Helms-Deaton J, Cordeiro-Stone M, Moore DT, Thomas NE, Hao H, Liu Z, Shields JM, Scott GA, Sharpless NE. Defective cell cycle checkpoint functions in melanoma are associated with altered patterns of gene expression. J Invest Dermatol 2008; 128:175-87. [PMID: 17597816 PMCID: PMC2753794 DOI: 10.1038/sj.jid.5700935] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Defects in DNA damage responses may underlie genetic instability and malignant progression in melanoma. Cultures of normal human melanocytes (NHMs) and melanoma lines were analyzed to determine whether global patterns of gene expression could predict the efficacy of DNA damage cell cycle checkpoints that arrest growth and suppress genetic instability. NHMs displayed effective G1 and G2 checkpoint responses to ionizing radiation-induced DNA damage. A majority of melanoma cell lines (11/16) displayed significant quantitative defects in one or both checkpoints. Melanomas with B-RAF mutations as a class displayed a significant defect in DNA damage G2 checkpoint function. In contrast the epithelial-like subtype of melanomas with wild-type N-RAS and B-RAF alleles displayed an effective G2 checkpoint but a significant defect in G1 checkpoint function. RNA expression profiling revealed that melanoma lines with defects in the DNA damage G1 checkpoint displayed reduced expression of p53 transcriptional targets, such as CDKN1A and DDB2, and enhanced expression of proliferation-associated genes, such as CDC7 and GEMININ. A Bayesian analysis tool was more accurate than significance analysis of microarrays for predicting checkpoint function using a leave-one-out method. The results suggest that defects in DNA damage checkpoints may be recognized in melanomas through analysis of gene expression.
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Affiliation(s)
- William K Kaufmann
- Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
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39
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Platz A, Egyhazi S, Ringborg U, Hansson J. Human cutaneous melanoma; a review of NRAS and BRAF mutation frequencies in relation to histogenetic subclass and body site. Mol Oncol 2007; 1:395-405. [PMID: 19383313 DOI: 10.1016/j.molonc.2007.12.003] [Citation(s) in RCA: 196] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2007] [Revised: 12/17/2007] [Accepted: 12/19/2007] [Indexed: 02/07/2023] Open
Abstract
A majority of cutaneous melanomas show activating mutations in the NRAS or BRAF proto-oncogenes, components of the Ras-Raf-Mek-Erk signal transduction pathway. Consistent data demonstrate the early appearance, in a mutually exclusive manner, of these mutations. The purpose of this paper is to summarize the literature on NRAS and BRAF activating mutations in melanoma tumors with respect to available data on histogenetic classification as well as body site and presumed UV-exposure. Common alterations of the signal transducing network seem to represent molecular hallmarks of cutaneous melanomas and therefore should continue to strongly stimulate design and testing of targeted molecular interventions.
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Affiliation(s)
- Anton Platz
- Department of Oncology-Pathology, Karolinska Institute, Cancer Centre Karolinska, Karolinska University Hospital Solna, Stockholm S-17176, Sweden
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40
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Nobeyama Y, Okochi-Takada E, Furuta J, Miyagi Y, Kikuchi K, Yamamoto A, Nakanishi Y, Nakagawa H, Ushijima T. Silencing of tissue factor pathway inhibitor-2 gene in malignant melanomas. Int J Cancer 2007; 121:301-7. [PMID: 17372906 DOI: 10.1002/ijc.22637] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
To identify tumor-suppressor genes inactivated by aberrant methylation of promoter CpG islands (CGIs) in human malignant melanomas, genes upregulated by treatment of cells with a demethylating agent, 5-aza-2'-deoxycytidine (5-aza-dC), were searched for using oligonucleotide microarrays in melanoma cell lines, HMV-I, MeWo and WM-115. Seventy-nine known genes with CGIs were identified as being upregulated (>or=16-fold), and 18 of them had methylation of their putative promoter CGIs in 1 or more of 8 melanoma cell lines. Among the 18 genes, TFPI-2, which is involved in repression of the invasive potential of malignant melanomas, was further analyzed. Its expression was repressed in a melanoma cell line with its complete methylation, and was restored by 5-aza-dC treatment. It was unmethylated in cultured neonatal normal epidermal melanocyte, and was induced by ultraviolet B. In surgical melanoma specimens, TFPI-2 methylation was detected in 5 of 17 metastatic site specimens (29%), while it was not detected in 20 primary site specimens (0%) (p=0.009). By immunohistochemistry, the 5 specimens with promoter methylation lacked immunoreactivity for TFPI-2. The results showed that TFPI-2 is silenced in human malignant melanomas by methylation of its promoter CGI and suggested that its silencing is involved in melanoma metastasis.
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Affiliation(s)
- Yoshimasa Nobeyama
- Carcinogenesis Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, Japan
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41
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Kramar F, Zemanova Z, Michalova K, Babicka L, Ransdorfova S, Hrabal P, Kozler P. Cytogenetic analyses in 81 patients with brain gliomas: correlation with clinical outcome and morphological data. J Neurooncol 2007; 84:201-11. [PMID: 17569001 DOI: 10.1007/s11060-007-9358-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2006] [Accepted: 02/16/2007] [Indexed: 11/27/2022]
Abstract
Specific gene mutations, loss of heterozygosity, deletions and/or amplifications of entire chromosomal regions and gene silencing have been described in gliomas. 82 samples from 81 patients were investigated to detect the deletion of TP53, RB1, CDKN2A genes, deletion of 1p36 and 19q13.3 region, amplification of EGFR gene, trisomy of chromosome 7 and monosomy of chromosome 10 in glial cells. Dual-colour interphase fluorescence in situ hybridization (I-FISH) with locus-specific and/or chromosome enumeration DNA probes were used for cytogenetic analyses. In the study, molecular cytogenetic analyses were successfully performed in 74 patients (91.3%) and were uninformative in 7 only (8.7%). The cytogenetic analyses were correlated with morphological data and clinical outcome. I-FISH was the essential part of diagnostics. In comparison with the clinical data, the patients' age seems to be a factor more important for the overall survival, rather than cytogenetic findings in glial tumours. The combined deletion of 1p36 and 19q13.3 chromosomal regions predicts longer overall survival for patients with oligodendroglial tumours.
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Affiliation(s)
- Filip Kramar
- Department of Neurosurgery, 1st Faculty of Medicine, Charles University and Central Military Hospital, Prague 16902, Czech Republic.
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42
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Shields JM, Thomas NE, Cregger M, Berger AJ, Leslie M, Torrice C, Hao H, Penland S, Arbiser J, Scott G, Zhou T, Bar-Eli M, Bear JE, Der CJ, Kaufmann WK, Rimm DL, Sharpless NE. Lack of extracellular signal-regulated kinase mitogen-activated protein kinase signaling shows a new type of melanoma. Cancer Res 2007; 67:1502-12. [PMID: 17308088 DOI: 10.1158/0008-5472.can-06-3311] [Citation(s) in RCA: 66] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The majority of human melanomas harbor activating mutations of either N-RAS or its downstream effector B-RAF, which cause activation of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase and the ERK MAPK cascade. The melanoma-relevant effectors of ERK activation, however, are largely unknown. In this work, we show that increased ERK activation correlates strongly with mutational status of N-RAS or B-RAF in 21 melanoma cell lines. Melanoma lines that were wild-type for RAS/RAF showed low levels of ERK activation comparable with primary human melanocytes. Through supervised analysis of RNA expression profiles, we identified 82 genes, including TWIST1, HIF1alpha, and IL-8, which correlated with ERK activation across the panel of cell lines and which decreased with pharmacologic inhibition of ERK activity, suggesting that they are ERK transcriptional targets in melanoma. Additionally, lines lacking mutations of N-RAS and B-RAF were molecularly distinct and characterized by p53 inactivation, reduced ERK activity, and increased expression of epithelial markers. Analysis of primary human melanomas by tissue microarray confirmed a high correlation among expression of these epithelial markers in a heterogeneous sample of 570 primary human tumors, suggesting that a significant frequency of primary melanomas is of this "epithelial-like" subtype. These results show a molecularly distinct melanoma subtype that does not require ERK activation or epithelial-mesenchymal transformation for progression.
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Affiliation(s)
- Janiel M Shields
- Department of Biochemistry and Biophysics, The Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA
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Jönsson G, Dahl C, Staaf J, Sandberg T, Bendahl PO, Ringnér M, Guldberg P, Borg A. Genomic profiling of malignant melanoma using tiling-resolution arrayCGH. Oncogene 2007; 26:4738-48. [PMID: 17260012 DOI: 10.1038/sj.onc.1210252] [Citation(s) in RCA: 85] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Malignant melanoma is an aggressive, heterogeneous disease where new biomarkers for diagnosis and clinical outcome are needed. We searched for chromosomal aberrations that characterize its pathogenesis using 47 different melanoma cell lines and tiling-resolution bacterial artificial chromosome-arrays for comparative genomic hybridization. Major melanoma genes, including BRAF, NRAS, CDKN2A, TP53, CTNNB1, CDK4 and PTEN, were examined for mutations. Distinct copy number alterations were detected, including loss or gain of whole chromosomes but also minute amplifications and homozygous deletions. Most common overlapping regions with losses were mapped to 9p24.3-q13, 10 and 11q14.1-qter, whereas copy number gains were most frequent on chromosomes 1q, 7, 17q and 20q. Amplifications were delineated to oncogenes such as MITF (3p14), CCND1 (11q13), MDM2 (12q15), CCNE1 (19q12) and NOTCH2 (1p12). Frequent findings of homozygous deletions on 9p21 and 10q23 confirmed the importance of CDKN2A and PTEN. Pair-wise comparisons revealed distinct sets of alterations, for example, mutually exclusive mutations in BRAF and NRAS, mutual mutations in BRAF and PTEN, concomitant chromosome 7 gain and 10 loss and concomitant chromosome 15q22.2-q26.3 gain and 20 gain. Moreover, alterations of the various melanoma genes were associated with distinct chromosomal imbalances suggestive of specific genomic programs in melanoma development.
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Affiliation(s)
- G Jönsson
- Department of Oncology, University Hospital, Lund, Sweden
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Koynova D, Jordanova E, Kukutsch N, van der Velden P, Toncheva D, Gruis N. Increased C-MYC copy numbers on the background of CDKN2A loss is associated with improved survival in nodular melanoma. J Cancer Res Clin Oncol 2006; 133:117-23. [PMID: 16977458 DOI: 10.1007/s00432-006-0150-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2006] [Accepted: 07/31/2006] [Indexed: 11/29/2022]
Abstract
PURPOSE In order to obtain better insight into the genetic background of nodular melanoma (NM), we aimed to analyse the frequency of CDKN2A and C-MYC copy number changes. The impact of these aberrations on the metastatic potential and patient's survival was considered. METHODS Fluorescent in situ hybridization was used to analyse the C-MYC and CDKN2A genes on isolated nuclei from 49 paraffin-embedded primary NMs. RESULTS Thirty-six (73.47%) melanoma samples showed CDKN2A deletion while 11 of these 36 (22.45%) additionally displayed C-MYC increased copy numbers. Cases positive for metastases more commonly displayed CDKN2A deletions. However, the combined C-MYC and CDKN2A aberrations were found predominantly in the non-metastasizing group of primary NM. The survival analysis furthermore demonstrated that patients with combined CDKN2A and C-MYC aberrations have a significantly better prognosis than carriers of CDKN2A deletion only. CONCLUSIONS We conclude that the C-MYC increased copy number changes on the background of CDKN2A deletions seem to be related to a low metastatic potential and better patients' outcome in primary NMs.
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Affiliation(s)
- Denitsa Koynova
- Department of Medical Genetics, Medical University Sofia, 2 Zdrave Str, 1431, Sofia, Bulgaria.
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Abstract
The landmark sequencing of the human genome has ushered in a new field of large-scale research. Advances in understanding the molecular basis of disease have opened up new opportunities to develop genomics-based tools to diagnose, predict disease onset or recurrence, tailor treatment options, and assess treatment response. Although still in the early stages of research and development, genomic biomarker research has the capability of providing a comprehensive insight into pathophysiological processes as well as more precise predictors of outcome not previously attainable with traditional biomarkers. Before genomic biomarkers are incorporated into clinical practice, several issues will need to be addressed in order to generate the necessary levels of evidence to demonstrate analytical and clinical validity and utility. In addition, efforts will be needed to educate health professionals and the public about genomics-based tools, revise regulatory oversight mechanisms, and ensure privacy safeguards of the information generated from these new tests.
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Affiliation(s)
- Geoffrey S Ginsburg
- Center for Genomic Medicine, Institute for Genome Sciences & Policy, Duke University, Box 3382, Durham, NC 27708, USA.
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