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- Title
Large-scale copy number alterations are enriched for synthetic viability in BRCA1/BRCA2 tumors.
- Authors
Zhu, Yingjie; Pei, Xin; Novaj, Ardijana; Setton, Jeremy; Bronder, Daniel; Derakhshan, Fatemeh; Selenica, Pier; McDermott, Niamh; Orman, Mehmet; Plum, Sarina; Subramanyan, Shyamal; Braverman, Sara H.; McMillan, Biko; Sinha, Sonali; Ma, Jennifer; Gazzo, Andrea; Khan, Atif; Bakhoum, Samuel; Powell, Simon N.; Reis-Filho, Jorge S.
- Abstract
Background: Pathogenic BRCA1 or BRCA2 germline mutations contribute to hereditary breast, ovarian, prostate, and pancreatic cancer. Paradoxically, bi-allelic inactivation of BRCA1 or BRCA2 (bBRCA1/2) is embryonically lethal and decreases cellular proliferation. The compensatory mechanisms that facilitate oncogenesis in bBRCA1/2 tumors remain unclear. Methods: We identified recurrent genetic alterations enriched in human bBRCA1/2 tumors and experimentally validated if these improved proliferation in cellular models. We analyzed mutations and copy number alterations (CNAs) in bBRCA1/2 breast and ovarian cancer from the TCGA and ICGC. We used Fisher's exact test to identify CNAs enriched in bBRCA1/2 tumors compared to control tumors that lacked evidence of homologous recombination deficiency. Genes located in CNA regions enriched in bBRCA1/2 tumors were further screened by gene expression and their effects on proliferation in genome-wide CRISPR/Cas9 screens. A set of candidate genes was functionally validated with in vitro clonogenic survival and functional assays to validate their influence on proliferation in the setting of bBRCA1/2 mutations. Results: We found that bBRCA1/2 tumors harbor recurrent large-scale genomic deletions significantly more frequently than histologically matched controls (n = 238 cytobands in breast and ovarian cancers). Within the deleted regions, we identified 277 BRCA1-related genes and 218 BRCA2-related genes that had reduced expression and increased proliferation in bBRCA1/2 but not in wild-type cells in genome-wide CRISPR screens. In vitro validation of 20 candidate genes with clonogenic proliferation assays validated 9 genes, including RIC8A and ATMIN (ATM-Interacting protein). We identified loss of RIC8A, which occurs frequently in both bBRCA1/2 tumors and is synthetically viable with loss of both BRCA1 and BRCA2. Furthermore, we found that metastatic homologous recombination deficient cancers acquire loss-of-function mutations in RIC8A. Lastly, we identified that RIC8A does not rescue homologous recombination deficiency but may influence mitosis in bBRCA1/2 tumors, potentially leading to increased micronuclei formation. Conclusions: This study provides a means to solve the tumor suppressor paradox by identifying synthetic viability interactions and causal driver genes affected by large-scale CNAs in human cancers.
- Subjects
HOMOLOGOUS recombination; GENE expression; CELL proliferation; FISHER exact test; DNA repair; TUMOR suppressor genes
- Publication
Genome Medicine, 2024, Vol 16, Issue 1, p1
- ISSN
1756-994X
- Publication type
Article
- DOI
10.1186/s13073-024-01371-y