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

Wouters, Jasper; Vizoso, Miguel; Martinez-Cardus, Anna; Carmona, F Javier; Govaere, Olivier; Laguna, Teresa; Joseph, Jesuchristopher; Dynoodt, Peter; Aura, Claudia and Foth, Mona, et al. (2017) In BMC Medicine 15(1). p.1-16
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... (More)

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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@article{3e3b333f-8717-496d-a457-22458c3689ee,
  abstract     = {<p>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.</p>},
  articleno    = {101},
  author       = {Wouters, Jasper and Vizoso, Miguel and Martinez-Cardus, Anna and Carmona, F Javier and Govaere, Olivier and Laguna, Teresa and Joseph, Jesuchristopher and Dynoodt, Peter and Aura, Claudia and Foth, Mona and Cloots, Roy and van den Hurk, Karin and Balint, Balazs and Murphy, Ian G. and McDermott, Enda W. and Sheahan, Kieran and Jirström, Karin and Nodin, Bjorn and Mallya-Udupi, Girish and Van den Oord, Joost J and Gallagher, William M and Esteller, Manel},
  issn         = {1741-7015},
  keyword      = {Correlation of clinical and molecular markers,Melanoma/skin cancers,Molecular diagnosis and prognosis,Molecular markers of metastasis and progression,Tumor staging},
  language     = {eng},
  month        = {06},
  number       = {1},
  pages        = {1--16},
  publisher    = {BioMed Central},
  series       = {BMC Medicine},
  title        = {Comprehensive DNA methylation study identifies novel progression-related and prognostic markers for cutaneous melanoma},
  url          = {http://dx.doi.org/10.1186/s12916-017-0851-3},
  volume       = {15},
  year         = {2017},
}