Related Experiment Videos
Inactivation of BRCA1 and BRCA2 in ovarian cancer
Jeffrey L Hilton1, John P Geisler, Jennifer A Rathe
1Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Holden Comprehensive Cancer Center, Iowa City, IA, USA.
Background:
Although BRCA1 and BRCA2 play important roles in hereditary ovarian cancers, the extent of their role in sporadic ovarian cancers and their mechanisms of inactivation are not yet well understood. Our goal was to characterize BRCA2 mutations and mRNA expression in a group of ovarian tumors previously evaluated for BRCA1 mutations and mRNA expression.
Methods:
The tumors of 92 unrelated women with "ovarian" cancer (i.e., ovarian, peritoneal, or fallopian tube cancer) were screened for BRCA2 null mutations using a protein truncation test. Methylation-specific polymerase chain reaction (PCR) was used to examine the BRCA2 promoter for hypermethylation in tumors that did not express BRCA2 mRNA. All statistical tests were two-sided.
Results:
Nine tumors had a germline (n = 5) or somatic (n = 4) BRCA2 mutation; each was associated with loss of heterozygosity. All of the somatic (1445delC, E880X, 4286del8, and 5783delT) and one of the germline (5984ins4) mutations were unique to this study. One tumor had somatic mutations in both BRCA1 and BRCA2. Two tumors are, to our knowledge, the first cases of germline BRCA2-associated peritoneal cancer. Twelve additional tumors lacked detectable BRCA2 mRNA, but the BRCA2 promoter was hypermethylated in only one of them, suggesting that other mechanisms effect transcriptional silencing of BRCA2. Tumors lacking BRCA1 mRNA were more likely to lack BRCA2 mRNA than tumors expressing BRCA1 mRNA (P<.001). Overall, 82% (95% confidence interval [CI] = 74% to 90%) of the tumors contained alterations in BRCA1, BRCA2, or both genes. Of 41 informative tumors with some alteration in BRCA2, 36 also had an alteration in BRCA1. The frequency, but not the mechanism, of BRCA1 or BRCA2 dysfunction in ovarian cancer was independent of family history.
Conclusions:
Multiple mechanisms cause nearly universal dysfunction of BRCA1 and/or BRCA2 in hereditary and sporadic ovarian carcinoma. Ovarian cancers with BRCA2 dysfunction often have simultaneous BRCA1 dysfunction.
Insights
Nearly all ovarian cancers show BRCA1 and/or BRCA2 gene dysfunction due to various mechanisms. Ovarian cancers with BRCA2 issues frequently also have BRCA1 issues, impacting hereditary and sporadic cases.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- BRCA1 and BRCA2 genes are crucial in hereditary ovarian cancers.
- Their role and inactivation mechanisms in sporadic ovarian cancers are not fully understood.
Purpose of the Study:
- To characterize BRCA2 mutations and mRNA expression in ovarian tumors.
- To investigate the role of BRCA2 in sporadic ovarian cancers.
Main Methods:
- Screening 92 ovarian tumors for BRCA2 mutations using protein truncation test.
- Examining BRCA2 promoter hypermethylation via methylation-specific PCR in tumors lacking BRCA2 mRNA.
Main Results:
- Nine tumors exhibited germline (5) or somatic (4) BRCA2 mutations.
- 82% of tumors showed alterations in BRCA1, BRCA2, or both.
- 36 of 41 tumors with BRCA2 alterations also had BRCA1 alterations.
Conclusions:
- Multiple mechanisms lead to widespread BRCA1/2 dysfunction in ovarian carcinoma.
- BRCA2 dysfunction in ovarian cancer often co-occurs with BRCA1 dysfunction.