BRCA1 mutation site may associate with nuclear DNA content in BRCA1-associated ovarian carcinomas

Abstract

5040 Background:In vitro studies suggest that BRCA1 has a role in maintaining normal nuclear DNA content during cell division and that BRCA1 inactivation may result in DNA aneuploidy and cancer progression. BRCA1-linked breast cancers are more aneuploid and have a worse prognosis compared with sporadic ones. To date, there have been no published reports comparing the DNA content of BRCA1-linked ovarian cancers with sporadic cases. In this study, we investigated the potential association between BRCA1 mutations and DNA aneuploidy in BRCA1-linked ovarian cancers, and compared DNA content in BRCA1-linked tumors with matched sporadic ovarian cancers. Methods: Tumor blocks from 21 BRCA1-associated ovarian cancers were matched with 21 sporadic ovarian carcinomas for histologic subtype, patient age, stage and grade (potential factors which may influence tumor cell DNA content). Nuclei DNA content was measured by Feulgen-Schiff staining and image cytometry. Results: Out of 18 informative BRCA1-linked tumors, 6/6 (100%) with a stop codon between 1–500 aa of the BRCA1 protein had a significantly higher frequency of non-diploidy compared with those with stop codon above 500 aa (7/12, 58%)(p=0.033). A diploid peak was detected in 28% of BRCA1-associated and 33% of sporadic ovarian cancers. No significant difference between the two study groups with respect to their DNA content was observed. Conclusions: BRCA1-associated ovarian tumors with a stop codon closer to the N-terminus of the BRCA1 protein may have a higher risk of DNA aneuploidy. Although it is tempting to postulate that BRCA1 mutations resulting in a stop codon prior to 500 aa may have a worse prognosis, this needs to be formally tested in a larger, prospectively-collected population. No significant financial relationships to disclose.