Allelic imbalance in BRCA1 and BRCA2 gene expression and familial ovarian cancer

Background: Family history is the strongest risk factor for ovarian cancer. Recent evidence suggests that unidentified BRCA1/2 variations or other genetic events may contribute to familial ovarian cancers. Allelic imbalance (AI) of BRCA1/2 expression, a result of a significant decrease in the ratios between the expression from one allele of BRCA1/2 and the other allele, has been observed in breast cancer. The AI of BRCA1/2 expression could decrease the level of transcripts and thus contribute to an increased susceptibility of developing familial ovarian cancer. Methods: To test this hypothesis, we applied a quantitative, allelic-specific, real-time PCR method to survey the levels of AI in BRCA1/2 in lymphoblastoid cell lines (LCL) from 126 familial ovarian cancer patients who are noncarriers of any known BRCA1/2 and MLH/MSH mutations and 118 cancer-free relative controls. Results: The AI ratios of BRCA1,but not BRCA2, in the LCLs from familial ovarian cancer patients were found to be significantly increased as compared with familycontrols(BRCA1:0.463 ± 0.054 vs. 0.405 ± 0.111, P = 0.0007; BRCA2:0.325 ± 0.124 vs. 0.302 ± 0.118, P = 0.328). Using the cutoff point of 0.458 identified from the receiver operating characteristic (ROC) analysis, higher levels of AI were associated with a 4.22-fold increased risk of familial ovarian cancer (95% CI: 1.60-11.16). In further analysis, we observed that levels of AI were negatively significantly correlated with the age of familial ovarian cancer diagnosis (p = -0.469, P < 0.001). Conclusion: Taken together, our data suggest that AI affecting BRCA1 may contribute to familial ovarian cancer. Cancer Epidemiol Biomarkers Prev; 20(1); 50-6.