Abstract P2-07-01: Polymorphism A247S of XRCC4 contributes to the risk of breast cancer and impairs DNA damage repair pathway

Abstract

Abstract Genetic variations in a network of genes involved in DNA double strand breaks (DSB) repair pathway have been shown to increase the risk of breast cancer. XRCC4 is identified as a pivotal modulator in non-homologous end joining (NHEJ), a predominant DSB repair pathway. In this study, we evaluated the associations between single nucleotide polymorphisms (SNPs) in XRCC4 and breast cancer, and investigated the impact of XRCC4A247S variant on nuclear localization and DNA damage response functions of XRCC4. A hospital-based case-control study, comprising 412 breast cancer patients and 458 cancer-free controls recruited from Shanghai Cancer Center, was conducted to investigate the relationship between common polymorphisms in XRCC4 and the risk of breast cancer. Our results showed that XRCC4A247S polymorphism (rs3734091), located near the putative nuclear localization signal (NLS) of XRCC4, was associated with a significantly increased risk of breast cancer in a recessive genetic model (Adjusted odds ratio (OR) = 1.47, 95% confidence interval (CI) = 1.09-4.52; P = 0.042). This homogeneous variant was more often observed in triple negative subtype (Adjusted OR = 2.07, 95% CI = 1.34 - 3.58 in the recessive model; P = 0.036). Although XRCC4A247S variant did not harm its interactions with XLF and ligase IV (the other two components of DNA ligase complex), we revealed that A247S alteration partially impaired the nuclear localization of XRCC4 in mammary cells. Remarkably, more evidences implied that XRCC4A247S variant significantly reduced the in vivo NHEJ repair efficiency compared to the wild-type XRCC4 via colony formation assay and NHEJ reporter assay, suggesting that reduced nuclear accumulation by XRCC4A247S variant impaired its functions in response to DNA damage. Importantly, XRCC4A247S alternation promoted cellular sensitivity to ionizing radiation and DNA damaging agents in chemotherapy. Taken together, this study demonstrates that genetic variation of XRCC4A247S could impair NHEJ mediated DSB repair and provide further evidences that genetic variants involved in DNA repair pathways contribute to breast cancer susceptibility. In addition, our results also indicate that XRCC4A247S variant might be a potential predictive biomarker and therapeutic target in breast cancer. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-07-01.