Abstract
Abstract Introduction/Purpose: The average age of diagnosis of melanoma is younger than that of other major cancers. In addition, melanoma is the second most common cancer among individuals in their 20s. Analyzing GWAS data by ‘wide-locus region’ (i.e. analyzing multiple nearby single nucleotide polymorphisms (SNPs) together) increases statistical power compared to single-SNP analyses. This approach has uncovered new associations in GWAS data for diseases other than melanoma. By applying wide-locus analysis to GWAS data from melanoma cases, we aimed to discover common genetic risk variants related to age of melanoma onset. Procedures: We re-analyzed data from the 1977 melanoma cases of European ancestry made available by the MD Anderson Cancer Center study (accession: phs000187.v1.p1). Patients were genotyped on the Illumina OMNI1-Quad chip. Biostatistical analysis was performed from a window moving across the whole genome using u-statistics for multivariate, genetically structured wide-locus data to derive genetic risk scores to determine if any gene regions were associated with age of onset in melanoma patients. This statistical approach resulted in a genome-wide significance level of p<10−5.64. Results: Common variants in several genes were associated with melanoma age-of-onset at the level of genome-wide significance. The most significant functional risk loci were located at DLEU1 (p<10−6.75), NRP1 (p<10−6.66), PTPN11P (p<10−6.49) and BAT1/ATP6/NFKBIL (p<10−6.41). Of note, none of these risk loci have been shown to be associated with risk of developing melanoma overall, or longevity in prior GWAS. The NRP1 and PTPN11P genes have been linked to the RAS pathway, an important driver of melanoma pathogenesis. Conclusions: Our analysis revealed novel associations between several common genetic variants and earlier age of melanoma diagnosis. Some of these loci interact with the RAS pathway. Additional studies of common genetic variants and age of cancer diagnosis using this approach may reveal similar findings in other melanoma cohorts and possibly other cancer types. Citation Format: Rachel M. Cymerman, Benedetta Bigio, Martin P. Seybold, David Polsky, Knut M. Wittkowski. Analysis of melanoma GWAS data suggests specific risk loci influencing age of onset of melanoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4628. doi:10.1158/1538-7445.AM2015-4628
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