Rare Variant, Gene-Based Association Study of Hereditary Melanoma Using Whole-Exome Sequencing.

J Natl Cancer Inst
Authors
Keywords
Abstract

Background: Extraordinary progress has been made in our understanding of common variants in many diseases, including melanoma. Because the contribution of rare coding variants is not as well characterized, we performed an exome-wide, gene-based association study of familial cutaneous melanoma (CM) and ocular melanoma (OM).

Methods: Using 11 990 jointly processed individual DNA samples, whole-exome sequencing was performed, followed by large-scale joint variant calling using GATK (Genome Analysis ToolKit). PLINK/SEQ was used for statistical analysis of genetic variation. Four models were used to estimate the association among different types of variants. In vitro functional validation was performed using three human melanoma cell lines in 2D and 3D proliferation assays. In vivo tumor growth was assessed using xenografts of human melanoma A375 melanoma cells in nude mice (eight mice per group). All statistical tests were two-sided.

Results: Strong signals were detected for CDKN2A (Pmin = 6.16 × 10-8) in the CM cohort (n = 273) and BAP1 (Pmin = 3.83 × 10-6) in the OM (n = 99) cohort. Eleven genes that exhibited borderline association (P

Conclusions: The results of this large rare variant germline association study further define the mutational landscape of hereditary melanoma and implicate EBF3 as a possible CM predisposition gene.

Year of Publication
2017
Journal
J Natl Cancer Inst
Volume
109
Issue
12
Date Published
2017 12 01
ISSN
1460-2105
DOI
10.1093/jnci/djx083
PubMed ID
29522175
PubMed Central ID
PMC5939858
Links
Grant list
12-0023 / AICR_ / Worldwide Cancer Research / United Kingdom
K24 CA149202 / CA / NCI NIH HHS / United States