Wouters Jasper, Vizoso Miguel, Martinez-Cardus Anna, Carmona F Javier, Govaere Olivier, Laguna Teresa, Joseph Jesuchristopher, Dynoodt Peter, Aura Claudia, Foth Mona, Cloots Roy, van den Hurk Karin, Balint Balazs, Murphy Ian G, McDermott Enda W, Sheahan Kieran, Jirström Karin, Nodin Bjorn, Mallya-Udupi Girish, van den Oord Joost J, Gallagher William M, Esteller Manel
Translational Cell and Tissue Research, KU Leuven (University of Leuven), Leuven, Belgium.
OncoMark Ltd, NovaUCD, Dublin 4, Ireland.
BMC Med. 2017 Jun 5;15(1):101. doi: 10.1186/s12916-017-0851-3.
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.
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.
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.
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.
皮肤黑色素瘤是最致命的皮肤癌，其发病率和死亡率呈上升趋势。目前，原发性黑色素瘤患者的分期是使用组织学生物标志物，如肿瘤厚度和溃疡情况。由于表观基因组格局的破坏被认为是肿瘤发生和发展中固有的普遍特征，我们旨在通过无偏倚的全基因组DNA甲基化分析，识别出能提供超越当前因素的额外临床信息的新型生物标志物。
我们使用Infinium HumanMethylation450 BeadChips对良性痣（n = 14）以及来自原发性（n = 33）和转移性（n = 28）部位的恶性黑色素瘤的发现队列进行了黑色素瘤所有进展阶段的全面DNA甲基化分析，并将DNA甲基化组与基因表达数据整合。我们通过焦磷酸测序和免疫组织化学在三个独立的验证队列中验证了发现的生物标志物。
我们识别并验证了黑色素瘤发生（如HOXA9 DNA甲基化）和肿瘤进展（如TBC1D16 DNA甲基化）相关的生物标志物及相关通路。此外，我们确定了一个具有潜在临床适用性的预后特征，并验证了PON3 DNA甲基化和OVOL1蛋白表达作为具有独立于肿瘤厚度和溃疡情况的预后信息的生物标志物。
我们的数据强调了表观基因组调控在通过使核心癌症相关通路失活触发转移扩散中的重要性。细胞粘附和分化的失活引发扩散，随后炎症和免疫系统程序的激活损害抗肿瘤防御通路。此外，我们识别出了几种先前与黑色素瘤无关的肿瘤发生和进展标志物，并确定了一个具有潜在临床效用的预后特征。
