Prevalent Loss Of Brca1 And Brca2 Expression In African Tnbc Suggests Their Prominent Role In Sporadic Carcinogenesis

BRCAness is a property shared by breast tumors with sporadic BRCA1 mutations or arising in patients with germline BRCA1 mutations, or tumors which down-regulate BRCA1 expression by other mechanisms. Women with African ancestry have been shown to have breast tumors that have characteristics similar to BRCA mutated tumors, but there is scant data on the signaling and regulation of the BRCA1 and BRCA 2 pathways in theses tumors. We have hypothesized that defective expression of key players in the BRCA1 and BRCA2 pathways may contribute to the BRCAness observed in sporadic breast cancers in women with African ancestry. Method: 1. Genomic and transcriptomic studies using Next Generation Sequencing technologies of normal DNA extracted from saliva and tumor DNA and RNA, extracted from frozen tumors were performed on four triple negative breast cancer (TNBC) specimens from Ghanaian women. Whole exome sequencing and RNA-sequencing (RNA-seq) were completed on all patients. 2. Immunohistochemistry staining for BRCA1, BRCA2 and PALB2 protein was completed for 49 Ghanaian TNBC tumor samples. IHC staining was also performed on some of the tumors that were sequenced. IHC staining was performed on PDX tumors derived from Ghanaian TNBC. 3. Generation of patient derived xenografts (PDX) models of TNBC from Ghanaian breast cancer patients for sequencing, q and standard PCR, and Western blot to determine the signaling of BRCA1 and BRCA2 pathway in Ghanaian TNBCs. Results: We discovered novel BRCA2 nonsense variant that will likely result in truncation or no expression. This tumor did not show BRCA2 expression on IHC. All the patients who had previously reported BRCA1 and BCRA2 variants had no expression of the proteins on IHC. Of the 49 Ghanaian TNBC tumors that were stained for BRCA1 and BRCA2, half did not express either BRCA1 or BRCA2, 10% had no expression of BRCA1 alone and none had loss of BRCA2 expression alone. Studies are ongoing on the PDX models to identify the expression of members of the BRCA1 and BRCA2 pathways in TNBC of women with African ancestry. Conclusion: A large proportion of TNBCs from African women have loss of expression of BRCA1 and BRCA2. Identifying the signaling alterations in the BRCA1 and BRCA2 pathways may help to identify novel drug targets for TNBC or may help predict response to PARP inhibitors or related drugs. IHC is an important and relatively inexpensive method for determining patients with BRCA pathway alteration who my benefit from DNA repair targeted therapy. This will be very beneficial for women in Africa who do not have access to BCRA germline testing. Citation Format: Evelyn M. Jiagge, Shukmei Wong, Gabriel Lupu, Mu Qiao, Michele Dziubinski, Lisa A. Newman, John Carpten, Max Wicha, Sofia D. Merajver. Prevalent loss of BRCA1 and BRCA2 expression in African TNBC suggests their prominent role in sporadic carcinogenesis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3852. doi:10.1158/1538-7445.AM2015-3852