Abstract 2634: Polymorphisms in DNA repair genes and risk of multiple myeloma

Abstract

Abstract Background and Objective: DNA repair is an essential process for development and differentiation of all cells, including plasma cells. Associations between single nucleotide polymorphisms (SNPs) in DNA repair genes and multiple myeloma risk have been reported but generally not replicated. In a pilot study, we observed suggestive evidence of an association between multiple myeloma risk and five nonsynonymous SNPs in DNA repair genes (rs25489 in XRCC1, rs1801516 in ATM, rs2227999 in XPC, rs2228528 in CSB and rs2228615 in ICAM5). The objective of this study was to examine the effect of these five SNPs on multiple myeloma risk in a large multi-center analysis. Methods: We conducted a pooled analysis in a multi-ethnic sample of 489 multiple myeloma cases and 939 controls. Studies contributing samples included two population-based case-control studies conducted in Los Angeles and Seattle/Detroit that used the Surveillance, Epidemiology and End Results (SEER) cancer registries to identify cases, and three nested case-control studies using subjects from the Multiethnic Cohort (MEC), the Health Professionals Follow Up Study (HPFS), and the Nurses’ Health Study (NHS). The SNPs coded for an amino acid substitution, and were assumed to have the same effect across ethnic groups, and thus subjects from all racial/ethnic groups were included in the analysis. Assuming a log-additive inheritance model, odds ratios (OR) and 95% confidence intervals (95% CIs) were calculated for allele-specific risk comparing cases to controls using unconditional logistic regression, adjusting for age, race/ethnicity, sex, and study site. Results: We observed a 40% decreased risk per variant T allele in the XRCC1 SNP rs25489 (OR=0.60, 95% CI=0.40, 0.91, p-value=0.02). The minor allele frequency in cases and controls was 3.4% and 5.6%, respectively. Non-significant OR's < 1.0 were observed when whites (OR=0.67, 95% CI=0.38, 1.17) and African Americans (OR=0.33, 95% CI= 0.09, 1.20) were considered separately. The SNPs in other DNA repair genes, ATM (rs1801516), XPC (rs2227999), CSB (rs2228528) and ICAM5 (rs2228615), showed no association with multiple myeloma risk. Conclusion: We observed an association between multiple myeloma and XRCC1, a gene that encodes a protein involved in the repair of single-stranded DNA breaks caused by ionizing radiation and alkylating agents. The variant allele of rs25489 results in a missense mutation substituting an amino acid (Arg > His). Several studies have shown diminished DNA repair capacity associated with the variant allele of this SNP, an effect which may be relevant to multiple myeloma etiology. Replication in additional studies is needed to validate this finding. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2634. doi:1538-7445.AM2012-2634