Telomere Length Genes Are Associated With Melanoma Risk
Longer telomeres have been associated with increased risk of melanoma. In a GenoMEL Consortium genome-wide association study reported in the Journal of the National Cancer Institute, Iles et al found that several single-nucleotide polymorphisms (SNPs) previously associated with leukocyte telomere length were significantly associated with risk of melanoma.
Study Details
The study involved analysis of seven SNPs previously identified as associated with telomere length in 11,108 case patients and 13,933 controls from Europe, Israel, United States, and Australia. The seven SNPs were rs10936599 in the TERC gene, rs2736100 in TERT, rs7675998 in NAF1, rs9420907 in OBFC1, rs8105767 in ZNF208, rs755017 in RTEL1, and rs11125529 in ACYP2. All were genotyped or well-imputed in melanoma samples.
Significant Associations
Of the seven SNPs, four had nominal statistically significant associations with melanoma risk, consisting of those in TERC (P = .0003), TERT (P = .02), NAF1 (P = .03), and OBFC1 (P = .001). The telomere-associated SNPs in TERC, TERT, OBFC1, and RTEL1 are located near other SNPs that were associated with melanoma risk in another study; additional analysis suggested that the two studies may have identified the same underlying signal in these regions.
Longer Telomere Length
The allele associated with decreased telomere length was more frequent in controls for all telomere-associated SNPs but the least statistically significant SNP (ACYP2), a finding consistent with a protective role of shorter telomeres in melanoma. The estimated effects of the seven SNPs on telomere length and melanoma risk were highly correlated (Pearson’s correlation = 0.92, P = .002). A genetic score that predicts telomere length based on the seven SNPs showed a highly significant association between increased score and melanoma risk (P = 8.92 × 10-9), with this association being observed in all geographic regions.
The investigators concluded: “This [study] demonstrates that the previously observed association between longer telomere length and increased melanoma risk is not attributable to confounding via shared environmental effects (such as ultraviolet exposure) or reverse causality [ie, cancer causing the increased length]. We provide the first proof that multiple germline genetic determinants of telomere length influence cancer risk.”
Mark M. Iles, MSc, PhD, of St James’s University Hospital, Leeds, is the corresponding author for the Journal of the National Cancer Institute article.
The GenoMEL study is supported by the European Commission 6th Framework Programme, Cancer Research UK, US National Institutes of Health, US National Cancer Institute, Wellcome Trust, and many others. For full disclosures of the study authors, visit jnci.oxfordjournals.org.
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