Comprehensive DNA methylation study identifies novel progression-related and prognostic markers for cutaneous melanoma
Autor: | Olivier Govaere, Teresa Laguna, Mona Foth, F. Javier Carmona, Karin Jirström, Balázs Bálint, Kieran Sheahan, Manel Esteller, William M. Gallagher, Joost van den Oord, Girish Mallya-Udupi, Anna Martínez-Cardús, Roy Cloots, Claudia Aura, Jasper Wouters, Jesuchristopher Joseph, Ian G. Murphy, Peter Dynoodt, Karin van den Hurk, Björn Nodin, Miguel Vizoso, Enda W. McDermott |
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Přispěvatelé: | Promovendi NTM, RS: GROW - R2 - Basic and Translational Cancer Biology, Universitat de Barcelona |
Jazyk: | angličtina |
Rok vydání: | 2017 |
Předmět: |
0301 basic medicine
Male Skin Neoplasms ADN lcsh:Medicine Bioinformatics UP-REGULATION MALIGNANT-MELANOMA EXPRESSION PROFILES Melanoma/skin cancers 0302 clinical medicine Skin cancer PROMOTER METHYLATION METASTATIC MELANOMA TUMOR PROGRESSION Melanoma Epigenomics Aged 80 and over Molecular markers of metastasis and progression General Medicine DNA Neoplasm Middle Aged Prognosis 3. Good health GENOME 030220 oncology & carcinogenesis Tumor markers DNA methylation Disease Progression Immunohistochemistry Epigenetics Female Metilació Research Article Adult CELL-LINES Molecular diagnosis and prognosis Methylation 03 medical and health sciences Breast cancer medicine Biomarkers Tumor Humans BREAST-CANCER Càncer de pell Aged POLYMERASE-1 business.industry Marcadors tumorals lcsh:R DNA DNA Methylation Tumor staging medicine.disease Epigenètica Correlation of clinical and molecular markers 030104 developmental biology Tumor progression Cutaneous melanoma Cancer research business |
Zdroj: | BMC Medicine, Vol 15, Iss 1, Pp 1-16 (2017) BMC Medicine, 15:101. BioMed Central Ltd BMC Medicine Dipòsit Digital de la UB Universidad de Barcelona Recercat. Dipósit de la Recerca de Catalunya instname |
ISSN: | 1741-7015 |
Popis: | Background Cutaneous melanoma is the deadliest skin cancer, with an increasing incidence and mortality rate. Currently, staging of patients with primary melanoma is performed using histological biomarkers such as tumor thickness and ulceration. As disruption of the epigenomic landscape is recognized as a widespread feature inherent in tumor development and progression, we aimed to identify novel biomarkers providing additional clinical information over current factors using unbiased genome-wide DNA methylation analyses. Methods We performed a comprehensive DNA methylation analysis during all progression stages of melanoma using Infinium HumanMethylation450 BeadChips on a discovery cohort of benign nevi (n = 14) and malignant melanoma from both primary (n = 33) and metastatic (n = 28) sites, integrating the DNA methylome with gene expression data. We validated the discovered biomarkers in three independent validation cohorts by pyrosequencing and immunohistochemistry. Results We identified and validated biomarkers for, and pathways involved in, melanoma development (e.g., HOXA9 DNA methylation) and tumor progression (e.g., TBC1D16 DNA methylation). In addition, we determined a prognostic signature with potential clinical applicability and validated PON3 DNA methylation and OVOL1 protein expression as biomarkers with prognostic information independent of tumor thickness and ulceration. Conclusions Our data underscores the importance of epigenomic regulation in triggering metastatic dissemination through the inactivation of central cancer-related pathways. Inactivation of cell-adhesion and differentiation unleashes dissemination, and subsequent activation of inflammatory and immune system programs impairs anti-tumoral defense pathways. Moreover, we identify several markers of tumor development and progression previously unrelated to melanoma, and determined a prognostic signature with potential clinical utility. Electronic supplementary material The online version of this article (doi:10.1186/s12916-017-0851-3) contains supplementary material, which is available to authorized users. |
Databáze: | OpenAIRE |
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