Genome-wide DNA methylation profile of leukocytes from melanoma patients with and without CDKN2A mutations

Abstract

Melanoma is a highly aggressive cancer, accounting for up to 75% of skin cancer deaths. A small proportion of melanoma cases can be ascribed to the presence of highly penetrant germline mutations, and approximately 40% of hereditary melanoma cases are caused by CDKN2A mutations. The current study sought to investigate whether the presence of germline CDKN2A mutations or the occurrence of cutaneous melanoma would result in constitutive genome-wide DNA methylation changes. The leukocyte methylomes of two groups of melanoma patients (those with germline CDKN2A mutations and those without CDKN2A mutations) were analyzed together with the profile of a control group of individuals. A pattern of DNA hypomethylation was detected in the CDKN2A-negative patients relative to both CDKN2A-mutated patients and controls. Additionally, we delineated a panel of 90 CpG sites that were differentially methylated in CDKN2A-mutated patients relative to controls. Although we identified a possible constitutive epigenetic signature in CDKN2A-mutated patients, the occurrence of reported SNPs at the detected CpG sites complicated the data interpretation. Thus, further studies are required to elucidate the impact of these findings on melanoma predisposition and their possible effect on the penetrance of CDKN2A mutations.

LINE-1 hypermethylation in peripheral blood of cutaneous melanoma patients is associated with metastasis

“…CDKN2A is the most relevant known melanoma susceptibility gene, and mutations in this gene are more commonly detected in patients with a familial melanoma history 19 or with multiple primary melanomas 20 . In a preceding study, we investigated the genome-wide DNA methylation profile of CDKN2A mutation carriers, revealing in these melanoma patients few differentially methylated CpGs, which were mainly related to underlying single-nucleotide polymorphisms 21 . Thus, the hypermethylated pattern found in this group of CDKN2A mutation carriers appears to be restricted to repetitive sequences.…”

Death domain–associated protein DAXX regulates noncoding RNA transcription at the centromere through the transcription regulator ZFAT

“…Thus, roles of DAXX in cancer cells are dependent on the cellular contexts and gene expression profiles of cells, suggesting that the expression levels and/or mutations of DAXX-interacting partners may determine roles of DAXX in cancer cells. Interestingly, mutations in the ZFAT gene have also been found in several human cancers (25)(26)(27)(28)30,31). Furthermore, overexpression of ZFAT is observed in ovarian cancer (29).…”

“…On the other hand, various studies in human have reported that genetic variants of the ZFAT gene are associated with particular human diseases, including autoimmune thyroid diseases (20,21), aneurysms (22), hypertension (23), and type 2 diabetes mellitus (24). Furthermore, mutations and altered expression of the ZFAT gene are also observed in several human cancers (25)(26)(27)(28)(29)(30). For example, a genome-wide association study of diffuse large B cell lymphoma (DLBCL) patients showed that specific mutations in the ZFAT genes were strongly associated with poorer survival of DLBCL patients (31).…”

936 Quantitative genome-wide methylation analysis of high-grade non-muscle invasive bladder cancer

“…1. 25,26 On the basis of these criteria, a total of 1,057 CpGs, representing 256 genes, were identified as hypermethylated (b-value increase 0.4) in 15 or more of the 21 high-grade tumors, relative to their mean values in the normal bladder controls.…”