Abstract 2553: Characterization of rare germline variants in somatically mutated melanoma genes in melanoma-prone families.

Abstract

Abstract CDKN2A and CDK4 are the two major susceptibility genes for melanoma identified so far. However, these two genes only account for melanoma susceptibility in a small proportion of melanoma-prone families, suggesting the existence of other susceptibility genes. In addition, melanoma is among the tumors with the highest mutation rate and a large number of mutated genes have been identified that affect multiple key biological pathways. The goal of this study is to examine whether rare germline sequence variants and/or copy number variations (CNVs) in these genes may influence melanoma risk in melanoma-prone families without known CDKN2A/CDK4 mutations. Methods: We conducted exome sequencing in blood-derived DNA in 75 melanoma cases from 23 American melanoma families with ≥3 affected members. We evaluated rare non-synonymous variants, defined as allele frequency less than 0.1% reported in public databases (dbSNP, 1000 Genomes, or NHLBI's Exome Variant Server), in 37 genes (including BRAF, NRAS, KIT,PTEN, CDKN2A, GRIN2A, etc.) that are frequently mutated in melanoma. We also screened CNVs in these genes using data from the Nimblegen 3x720k exon-focused CGH tiling arrays, in which blood-derived DNA from 79 melanoma cases and 25 spouses were analyzed in the same mutation-negative families. We used the Nexus Copy Number™ built-in FASST2 algorithm to identify significant CNVs (significant threshold=0.000001; minimal number of probes per segment=5; log2 ratio>0.3 for gains and -0.3 for losses). Results: We identified 10 rare variants in 10 genes that showed partial/complete co-segregation with disease and were absent in our internal controls (N∼400). Four of these variants occurred in all cases within their respective families and 3 of them were novel. We did not identify any disease-related CNVs in these genes except for a deletion in exon 1β of CDKN2A/ p14ARF in 6 out of 7 melanoma cases in one big family. Our findings suggest that rare variants in somatically mutated genes may confer susceptibility to melanoma risk in a subset of families. However, these variants need to be validated, checked for functional relevance, and evaluated in a large number of cases and controls to determine their role in disease susceptibility. Citation Format: Xiaohong (Rose) Yang, Laura Burke, Kevin Jacobs, Michael Cullen, Joseph Boland, Laurie Burdett, Michael Malasky, Melissa Rotunno, Meredith Yeager, Stephen Chanock, Margaret Tucker, Alisa Goldstein. Characterization of rare germline variants in somatically mutated melanoma genes in melanoma-prone families. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2553. doi:10.1158/1538-7445.AM2013-2553