Abstract 66: Genetic predictors of DNA repair capacity in melanoma patients: A genome-wide approach.

Abstract

Abstract Cutaneous melanoma (CM) is the most serious form of skin cancer. DNA repair has been implicated in the etiology of CM in patients of xeroderma pigmentosum (XP), an autosomal recessive genetic disorder of DNA repair. We have reported that reduced cellular DNA repair capacity (DRC, as assessed by an in vitro lymphocyte-based assay) for removing UV-induced DNA damage is an independent risk factor for sporadic CM and may contribute to susceptibility to sunlight-induced CM in the general population. Recently, we completed a genome-wide association study (GWAS) of melanoma and we also have data on DRC phenotype measured as luciferase activity in the in vitro host-cell reactivation assay using study subjects' lymphocytes for 1042 CM patients. The life-style questionnaire data are also available for these patients included in the GWAS. This is a unique study population and opportunity for us to identify genetic predictors of DRC in CM patients using a genome-wide approach. We found that the DRC varies 6 folds among 1042 CM patients and that the history of sunburn modified the DRC levels. However, we did not find the significant difference within categories of other demographic, exposure and clinical factors including age, sex, smoking and drinking status, the presence of moles and dysplastic nevi, family history of any cancer in first-degree relatives, eye color, hair color, skin color, freckling in the sun as a child, tanning ability, tumor stage, thickness, clark level, ulceration and anatomic site. We applied a generalized linear model with SNPs as predictors and DRC (a continuous variable) as the outcome. The covariates of age, sex, DRC assay-related variables were adjusted in the model. Several suggestive loci contributing to the DRC phenotype have been identified at the significance level of 10−5, including rs1799787 (intron) and rs1799793 (codon 312) in ERCC2/XPD in all CM patients, and rs12342322 near RASEF in 931 CM patients with stage I – IV. The results indicate that DRC phenotype is genetically determined by the genes involved in the nucleotide excision repair pathway and that newly identified SNPs may help understand the underlying mechanism in DRC's role in CM initiation and progression [This work was supported by National Institute of Health grants R01CA100264 (Q. Wei), P50CA093459 (E. Grimm), and P30 CA016672 (The University of Texas M. D. Anderson Cancer Center)]. Citation Format: Li-E Wang, Hongliang Liu, Jeffrey E. Gershenwald, Victor G. Prieto, Elizabeth A. Grimm, Jeffery E. Lee, Christopher I. Amos, Qingyi Wei. Genetic predictors of DNA repair capacity in melanoma patients: A genome-wide approach. [abstract]. In: Proceedings of the AACR Special Conference on Post-GWAS Horizons in Molecular Epidemiology: Digging Deeper into the Environment; 2012 Nov 11-14; Hollywood, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(11 Suppl):Abstract nr 66.