Identifying genomic rearrangements in BRCA1 and BRCA2 in high-risk individuals for hereditary breast and ovarian cancer.

Abstract

163 Background: Germline mutations in the BRCA1 and BRCA2 genes are responsible for the majority of hereditary breast and ovarian cancer (HBOC). Comprehensive gene sequencing detects ~87% of BRCA mutations, and large genomic rearrangement testing (BART) accounts for ~3%. Criteria have been established to capture individuals who most likely have a BART mutation, however, recent data shows that some individuals have BART mutations and do not meet the criteria. We conducted a single-institution study to evaluate the sufficiency of BART criteria to determine if new criteria are warranted. Methods: During 2006-2008, 172 individuals underwent BRCA sequencing and BART at M. D. Anderson Cancer Center. A retrospective, IRB-approved chart review of a prospectively maintained database was conducted to determine BART criteria eligibility, personal/family history of breast and ovarian cancer and tumor characteristics. Univariate and multivariate analysis was performed to test the significance of each variable in relation to BRCA1/BRCA2 positivity. Results: Of 172 individuals, 12/34 (35%) had BRCA1 BART mutations, and 7/11 (64%) had BRCA2 BART mutations. Of the 19 individuals who tested positive for BART mutations, only 8 (42%) met BART criteria and 11 (58%) did not and proceeded with BART for various reasons (family history, insurance covered, and patient request). Individuals who were BRCA1 positive (sequencing or BART) were more likely to have ER/PR negative breast cancer (p<0.0001) and a personal (p=0.0215)/family history of ovarian cancer (p=0.0001) compared to non-carriers and individuals who had no family history Individuals who were BRCA1 sequencing positive were more likely to meet BART criteria than BRCA1 BART positive (p=0.0151) individuals. Conclusions: Given that no significant differences in family history/tumor characteristics between individuals who have sequencing and BART mutations were identified, and a majority of individuals who were BART positive do not meet BART criteria, it appears that these criteria may be insufficient. BART testing should be considered for all individuals who undergo BRCA sequencing; however, large scale collaboration studies should be conducted.

Smarcal1-Mediated Fork Reversal Triggers Mre11-Dependent Degradation of Nascent DNA in the Absence of Brca2 and Stable Rad51 Nucleofilaments

“…Maintenance of genome integrity during DNA replication relies on the ability to respond to DNA lesions and structures impairing replication fork progression ( Flynn and Zou, 2011 , Nam and Cortez, 2011 , Toledo et al., 2011 ). A central role in preventing genome instability commonly associated with human cancer is provided by the homologous recombination (HR) Brca1 and Brca2 genes, which are often mutated in sporadic and familial cases of cancers ( Holloman, 2011 , Jackson et al., 2011 ).…”