Higher Nevus Count Exhibits a Distinct DNA Methylation Signature in Healthy Human Skin: Implications for Melanoma
نویسندگان
چکیده
High nevus count is the strongest risk factor for melanoma, and although gene variants have been discovered for both traits, epigenetic variation is unexplored. We investigated 322 healthy human skin DNA methylomes associated with total body nevi count, incorporating genetic and transcriptomic variation. DNA methylation changes were identified at genes involved in melanocyte biology, such as RAF1 (P = 1.2 × 10-6) and CTC1 (region: P = 6.3 × 10-4), and other genes including ARRDC1 (P = 3.1 × 10-7). A subset exhibited coordinated methylation and transcription changes within the same biopsy. The total analysis was also enriched for melanoma-associated DNA methylation variation (P = 6.33 × 10-6). In addition, we show that skin DNA methylation is associated in cis with known genome-wide association study single nucleotide polymorphisms for nevus count, at PLA2G6 (P = 1.7 × 10-49) and NID1 (P = 6.4 × 10-14), as well as melanoma risk, including in or near MC1R, MX2, and TERT/CLPTM1L (P < 1 × 10-10). Our analysis using a uniquely large dataset comprising healthy skin DNA methylomes identified known and additional regulatory loci and pathways in nevi and melanoma biology. This integrative study improves our understanding of predisposition to nevi and their potential contribution to melanoma pathogenesis.
منابع مشابه
Higher Naevus Count Exhibits A Distinct DNA Methylation Signature in Healthy Human Skin: Implications for Melanoma
متن کامل
Expression of cyclooxygenase-2 in melanocytic skin lesions by immunohistochemistry
Introduction: cyclooxygenase-2 (COX-2) is involved in pathogenesis of various tumors and possibly malignant skin tumors including malignant melanoma; however, there is not enough information about COX-2 expression in benign melanocytic lesions. In the present study we compared the expression levels of COX-2 in malignant melanoma and benign melanocytic lesions. Method: In this analytical study, ...
متن کاملA new 12-gene diagnostic biomarker signature of melanoma revealed by integrated microarray analysis
Genome-wide microarray technology has facilitated the systematic discovery of diagnostic biomarkers of cancers and other pathologies. However, meta-analyses of published arrays often uncover significant inconsistencies that hinder advances in clinical practice. Here we present an integrated microarray analysis framework, based on a genome-wide relative significance (GWRS) and genome-wide global...
متن کاملClaudin11 Promoter Hypermethylation Is Frequent in Malignant Melanoma of the Skin, but Uncommon in Nevus Cell Nevi
Epigenetic inactivation of tumor-related genes is an important characteristic in the pathology of human cancers, including melanomagenesis. We analyzed the epigenetic inactivation of Claudin 11 (CLDN11) in malignant melanoma (MM) of the skin, including six melanoma cell lines, 39 primary melanoma, 41 metastases of MM and 52 nevus cell nevi (NCN). CLDN11 promoter hypermethylation was found in 19...
متن کاملComprehensive DNA methylation study identifies novel progression-related and prognostic markers for cutaneous melanoma
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 nove...
متن کامل