TY - JOUR
T1 - Comprehensive DNA methylation study identifies novel progression-related and prognostic markers for cutaneous melanoma
AU - Wouters, Jasper
AU - Vizoso, Miguel
AU - Martinez-Cardus, Anna
AU - Carmona, F. Javier
AU - Govaere, Olivier
AU - Laguna, Teresa
AU - Joseph, Jesuchristopher
AU - Dynoodt, Peter
AU - Aura, Claudia
AU - Foth, Mona
AU - Cloots, Roy
AU - van den Hurk, Karin
AU - Balint, Balazs
AU - Murphy, Ian G.
AU - McDermott, Enda W.
AU - Sheahan, Kieran
AU - Jirstrom, Karin
AU - Nodin, Bjorn
AU - Mallya-Udupi, Girish
AU - van den Oord, Joost J.
AU - Gallagher, William M.
AU - Esteller, Manel
PY - 2017/6/5
Y1 - 2017/6/5
N2 - 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.
AB - 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.
KW - Melanoma/skin cancers
KW - Molecular diagnosis and prognosis
KW - Molecular markers of metastasis and progression
KW - Tumor staging
KW - Correlation of clinical and molecular markers
KW - PROMOTER METHYLATION
KW - MALIGNANT-MELANOMA
KW - BREAST-CANCER
KW - UP-REGULATION
KW - METASTATIC MELANOMA
KW - EXPRESSION PROFILES
KW - TUMOR PROGRESSION
KW - CELL-LINES
KW - GENOME
KW - POLYMERASE-1
U2 - 10.1186/s12916-017-0851-3
DO - 10.1186/s12916-017-0851-3
M3 - Article
C2 - 28578692
SN - 1741-7015
VL - 15
JO - BMC Medicine
JF - BMC Medicine
IS - 1
M1 - 101
ER -