XPC as breast cancer susceptibility gene: evidence from genetic profiling, statistical inferences and protein structural analysis

Background: Gene polymorphisms that affect nucleotide excision repair (NER) pathway may link with higher susceptibility of breast cancer (BC); however, the significance of these associations may vary conferring to the individual ethnicity. Xeroderma pigmentosum complementation gene (XPC) plays a substantial role in recognizing damaged DNA during NER process. Objective and methods: To estimate the relationship among XPC polymorphisms and breast cancer (BC) risk, we carried out a case–control-association study with 493 BC cases and 387 controls using TETRA–ARMS-PCR. Distributional differences of clinical features, demographic factors and XPC polymorphisms among BC cases and controls were examined by conditional logistic regression model. Kaplan–Meier test was applied to predict survival distributions and protein structure was predicted using computational tools. Results: Obesity, consanguinity, positive marital status and BC family history were associated (P ≤ 0.01) with higher BC risk. Genotyping revealed significant involvement (P ≤ 0.01) of two XPC polymorphisms rs2228001–A > C (OR = 3.8; CI 1.9–7.6) and rs2733532–C > T (OR = 2.6; CI 1.4–5.03) in BC development, asserting them potential risk factors for increased BC incidence. However, no association (P > 0.05) was detected for overall or progression free survival for both XPC polymorphisms possibly due to shorter follow-up time (45 months). As compared to normal XPC structure, pronounced conformational changes have been observed in the C-terminus of XPC^Q939K, bearing rs2228001–A > C substitution. In XPC^Q939K, two additional α-helices were observed at A292-E297 and Y252-R286, while L623-M630 and L649-L653 helices were converted into loop conformation. Conclusion: In conclusion, both XPC polymorphisms confer significant association with increased BC risk. rs2228001 substitution may change the structural and functional preferences of XPC C-terminus, while rs2733532 may have regulatory role thereby leading to potential BC risk.