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 family controls (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 (ρ = -0.469, P < 0.001).


CONCLUSIONS
Taken together, our data suggest that AI affecting BRCA1 may contribute to familial ovarian cancer.
Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Elm and Carlton Streets, Basic Science 704, Buffalo, NY 14263, USA.
Jie
J
Shen
Leo
L
Medico
Hua
H
Zhao
D000328:Adult; D000368:Aged; D022981:Allelic Imbalance; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D015331:Cohort Studies; D005192:Family Health; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction