Constitutional promoter methylation and risk of familial melanoma.
Constitutional epigenetic changes detected in blood or non-disease involving tissues have been associated with disease susceptibility. We measured promoter methylation of CDKN2A (p16 and p14ARF) and 13 melanoma-related genes using bisulfite pyrosequencing of blood DNA from 114 cases and 122 controls in 64 melanoma-prone families (26 segregating CDKN2A germline mutations). We also obtained gene expression data for these genes using microarrays from the same blood samples. We observed that CDKN2A epimutation is rare in melanoma families, and therefore is unlikely to cause major susceptibility in families without CDKN2A mutations. Although methylation levels for most gene promoters were very low (<5%), we observed a significantly reduced promoter methylation (odds ratio = 0.63, 95% confidence interval = 0.50, 0.80, P<0.001) and increased expression (fold change = 1.27, P = 0.048) for TNFRSF10C in melanoma cases. Future research in large prospective studies using both normal and melanoma tissues is required to assess the significance of TNFRSF10C methylation and expression changes in melanoma susceptibility.
Division of Cancer Epidemiology and Genetics; National Cancer Institute; National Institutes of Health; Bethesda, MD USA; Cancer Prevention Fellowship Program; Division of Cancer Prevention; National Cancer Institute; National Institutes of Health; Bethesda, MD USA.
Paula L
PL
Hyland
Division of Cancer Epidemiology and Genetics; National Cancer Institute; National Institutes of Health; Bethesda, MD USA.
Laura S
LS
Burke
Division of Cancer Epidemiology and Genetics; National Cancer Institute; National Institutes of Health; Bethesda, MD USA.
Ruth M
RM
Pfeiffer
Division of Cancer Epidemiology and Genetics; National Cancer Institute; National Institutes of Health; Bethesda, MD USA.
Melissa
M
Rotunno
Laboratory of Molecular Technology; Scientific Application International Corporation Frederick; National Cancer Institute at Frederick; Frederick, MD USA.
David
D
Sun
Division of Cancer Epidemiology and Genetics; National Cancer Institute; National Institutes of Health; Bethesda, MD USA.
Prasad
P
Patil
Laboratory of Molecular Technology; Scientific Application International Corporation Frederick; National Cancer Institute at Frederick; Frederick, MD USA.
Xiaolin
X
Wu
Division of Cancer Epidemiology and Genetics; National Cancer Institute; National Institutes of Health; Bethesda, MD USA.
Margaret A
MA
Tucker
Division of Cancer Epidemiology and Genetics; National Cancer Institute; National Institutes of Health; Bethesda, MD USA.
Alisa M
AM
Goldstein
Division of Cancer Epidemiology and Genetics; National Cancer Institute; National Institutes of Health; Bethesda, MD USA.
Xiaohong Rose
XR
Yang
D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D018899:CpG Islands; D019175:DNA Methylation; D005260:Female; D058851:GPI-Linked Proteins / Q000235:genetics; D019942:Genes, p16; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics*; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D053320:Receptors, Tumor Necrosis Factor, Member 10c; D012306:Risk; D012878:Skin Neoplasms / Q000235:genetics*; D053319:Tumor Necrosis Factor Decoy Receptors / Q000235:genetics; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics; D000096142:Cutaneous Malignant Melanoma
D058851:GPI-Linked Proteins; D053320:Receptors, Tumor Necrosis Factor, Member 10c; C108661:TNFRSF10C protein, human; D053319:Tumor Necrosis Factor Decoy Receptors; D025803:Tumor Suppressor Protein p14ARF
CDKN2A; TNFRSF10C; familial melanoma; peripheral blood mononuclear cells; promoter methylation