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Open Access 01-12-2017 | Research article

Comprehensive DNA methylation study identifies novel progression-related and prognostic markers for cutaneous melanoma

Authors: Jasper Wouters, Miguel Vizoso, Anna Martinez-Cardus, F. Javier Carmona, Olivier Govaere, Teresa Laguna, Jesuchristopher Joseph, Peter Dynoodt, Claudia Aura, Mona Foth, Roy Cloots, Karin van den Hurk, Balazs Balint, Ian G. Murphy, Enda W. McDermott, Kieran Sheahan, Karin Jirström, Bjorn Nodin, Girish Mallya-Udupi, Joost J. van den Oord, William M. Gallagher, Manel Esteller

Published in: BMC Medicine | Issue 1/2017

Abstract

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.

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Title: Comprehensive DNA methylation study identifies novel progression-related and prognostic markers for cutaneous melanoma
Authors: Jasper Wouters
Miguel Vizoso
Anna Martinez-Cardus
F. Javier Carmona
Olivier Govaere
Teresa Laguna
Jesuchristopher Joseph
Peter Dynoodt
Claudia Aura
Mona Foth
Roy Cloots
Karin van den Hurk
Balazs Balint
Ian G. Murphy
Enda W. McDermott
Kieran Sheahan
Karin Jirström
Bjorn Nodin
Girish Mallya-Udupi
Joost J. van den Oord
William M. Gallagher
Manel Esteller
Publication date: 01-12-2017
Publisher: BioMed Central
Published in: BMC Medicine / Issue 1/2017
Electronic ISSN: 1741-7015
DOI: https://doi.org/10.1186/s12916-017-0851-3

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Comprehensive DNA methylation study identifies novel progression-related and prognostic markers for cutaneous melanoma

Abstract

Background

Methods

Results

Conclusions

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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