Large-scale copy number alterations are enriched for synthetic viability in BRCA1/BRCA2 tumors Journal Article
| Authors: | Zhu, Y.; Pei, X.; Novaj, A.; Setton, J.; Bronder, D.; Derakhshan, F.; Selenica, P.; McDermott, N.; Orman, M.; Plum, S.; Subramanyan, S.; Braverman, S. H.; McMillan, B.; Sinha, S.; Ma, J.; Gazzo, A.; Khan, A.; Bakhoum, S.; Powell, S. N.; Reis-Filho, J. S.; Riaz, N. |
| Article Title: | Large-scale copy number alterations are enriched for synthetic viability in BRCA1/BRCA2 tumors |
| 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. © The Author(s) 2024. |
| Keywords: | controlled study; human tissue; gene mutation; human cell; gene deletion; genetics; mutation; histopathology; cell proliferation; mitosis; ovarian neoplasms; gene; homologous recombination; dna repair; ovary cancer; breast cancer; gene expression; in vitro study; pathology; cell line, tumor; breast neoplasms; brca1 protein; brca2 protein; wild type; carcinogenesis; tumor suppressor gene; gene interaction; breast tumor; ovary tumor; tumor cell line; gene loss; clonogenic assay; loss of function mutation; brca1; brca1 protein, human; brca2; dna copy number variations; copy number variation; copy number alteration; micronucleus; tcga; copy number alterations; brca2 protein, human; humans; human; female; article; crispr-cas9 system; synthetic lethal mutations; crispr-cas9 knockout; icgc; synthetic viability; atmin gene; ric8a gene; synthetic lethal mutation |
| Journal Title: | Genome Medicine |
| Volume: | 16 |
| ISSN: | 1756-994X |
| Publisher: | Biomed Central Ltd |
| Date Published: | 2024-08-28 |
| Start Page: | 108 |
| Language: | English |
| DOI: | 10.1186/s13073-024-01371-y |
| PUBMED: | 39198848 |
| PROVIDER: | scopus |
| PMCID: | PMC11351199 |
| DOI/URL: | |
| Notes: | Article -- MSK corresponding author is Nadeem Riaz -- MSK author Shyamal Subramanyam's last name is misspelled on the original publication -- Source: Scopus |
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