Integrated case-control and somatic-germline interaction analyses of melanoma susceptibility genes.

Abstract

While a number of genes have been implicated in melanoma susceptibility, the role of protein-coding variation in melanoma development and progression remains underexplored. To better characterize the role of germline coding variation in melanoma, we conducted a whole-exome case-control and somatic-germline interaction study involving 322 skin cutaneous melanoma cases from The Cancer Genome Atlas and 3607 controls of European ancestry. We controlled for cross-platform technological stratification using XPAT and conducted gene-based association tests using VAAST 2. Four established melanoma susceptibility genes achieved nominal statistical significance, MC1R (p = .0014), MITF (p = .0165) BRCA2 (p = .0206), and MTAP (p = .0393). We also observed a suggestive association for FANCA (p = .002), a gene previously implicated in melanoma survival. The association signal for BRCA2 was driven primarily by likely gene disrupting (LGD) variants, with an Odds Ratio (OR) of 5.62 (95% Confidence Interval (CI) 1.03-30.1). In contrast, the association signals for MC1R and MITF were driven primarily by predicted pathogenic missense variants, with estimated ORs of 1.4 to 3.0 for MC1R and 4.1 for MITF. MTAP exhibited an excess of both LGD and predicted damaging missense variants among cases, with ORs of 5.62 and 3.72, respectively, although neither category was significant. For individuals with known or predicted damaging variants, age of disease onset was significantly lower for two of the four genes, MC1R (p = .005) and MTAP (p = .035). In an analysis of germline carrier status and overlapping copy number alterations, we observed no evidence to support a two-hit model of carcinogenesis in any of the four genes. Although MC1R carriers were represented proportionally among the four molecular tumor subtypes, these individuals accounted for 69% of ultraviolet (UV) radiation mutational signatures among triple-wild type tumors (p = .040), highlighting the increased sensitivity to UV exposure among individuals with loss-of-function variants in MC1R.

• Authors: Yao Yu, Hao Hu, Jiun-Sheng Chen, Fulan Hu, Jerry Fowler, Paul Scheet, Hua Zhao, Chad D Huff
• Journal: Biochimica et biophysica acta. Molecular basis of disease (Biochim Biophys Acta Mol Basis Dis) Vol. 1864 Issue 6 Pt B Pg. 2247-2254 (Jun 2018) ISSN: 0925-4439 [Print] Netherlands
• PMID: 29317335 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2018 Elsevier B.V. All rights reserved.

Chemical References

• Neoplasm Proteins

Topics

• Epistasis, Genetic
• Female
• Genetic Predisposition to Disease
• Germ-Line Mutation
• Humans
• Male
• Melanoma (genetics, metabolism)
• Mutation, Missense
• Neoplasm Proteins (genetics, metabolism)
• Skin Neoplasms (genetics, metabolism)