Abstract 4657: Identification and validation of genetic determinants of DNA repair phenotype in genome-wide association study of lung cancer
Authors: Li-E Wang, Olga Y. Gorlova, Jun Ying, Yawei Qiao, Margaret R. Spitz, Christopher I. Amos, Qingyi Wei
Journal: Cancer Research (2011)

Abstract DNA repair is essential in protecting the integrity of the genome. There is considerable inter-individual variation in DNA repair capacity (DRC). We have reported that cellular DRC (measured in lymphocytes using the host-cell reactivation assay with a reporter gene chloramphenicol acetyltransferase [CAT] damaged by an activated tobacco carcinogen, benzo(a)pyrene diol epoxide [BPDE]) modulates susceptibility to lung cancer. To identify genetic polymorphisms predictive of the repair phenotype, we used phenotype and genotype data in a population of 1,474 European ancestry individuals from a Texas lung cancer genome-wide association case-control study using Illumina 317K platform (317498 SNPs). This discovery phase was followed by replication testing of the top 20 SNPs in an independent set of an additional 1,364 European ancestry cases and controls, using Illumina Bead Array Platform. In addition, we performed a replication analysis of all SNPs with P &amp;lt; 0.01 in 145 DNA repair-related genes in BER, NER, MMR, DSBR pathways from the discovery set, and applying a conservative Bonferroni-corrected P -value of 2.37E-5 for the joint P -value, based on the total number of analyzed SNPs in DNA repair genes. The DRC data were divided into quartiles by assigning the top quarter of participants (with highest values of DRC) as the DNA repair proficient group and the bottom quarter of participants with lowest values of DRC as the suboptimal DRC group to enhance the contrast. We used a generalized linear model with SNPs as predictors and DRC as the outcome. The covariates age, gender, smoking status, duration of smoking, number of cigarettes per day, DRC assay-related variables including the sample storage time, baseline reporter gene CAT expression level, blastogenic rate, and the case-control status of the study participants were adjusted in the model. We identified several suggestive loci contributing to the DRC phenotype: rs9390123 in PHACTR2 (phosphatase and actin regulator 2, P = 4.78E-05 in the discovery set and P = 1.08E-05 in the joint analysis); rs4756897 in USH1C (Usher syndrome 1C, P = 5.40E-05 in the discovery set and 8.71E-06 in the joint analysis); rs6785626 in CNTN4 (contactin 4, P = 0.000451 in the discovery set and P = 1.55E-05 in the joint analysis); rs13181 in ERCC2 (excision repair cross-complementing rodent repair deficiency-complementation group 2, joint P = 2.09E-05); rs7443927 in DUSP1 (dual specificity phosphatase 1, joint P =5.04E-05) and rs10878361 in HMGA2 (high mobility group AT-hook 2, joint P =2.54E-4). In conclusion, we identified and replicated a number of SNPs associated with DRC. These genetic determinants of DNA repair phenotype are easier and cheaper to measure, and subject to less misclassification than the phenotype and may be effective biomarkers for risk assessment. (This study was supported by NIH grants CA127219, CA055769, ES011740, CA131274 and CA016672) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4657. doi:10.1158/1538-7445.AM2011-4657