NDLI: Large-scale copy number alterations are enriched for synthetic viability in BRCA1/BRCA2 tumors

Content Provider	Springer Nature : BioMed Central
Author	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. Riaz, Nadeem
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.
Related Links	https://genomemedicine.biomedcentral.com/counter/pdf/10.1186/s13073-024-01371-y.pdf
Ending Page	17
Page Count	17
Starting Page	1
File Format	HTM / HTML
DOI	10.1186/s13073-024-01371-y
Journal	Genome Medicine
Issue Number	1
Volume Number	16
Language	English
Publisher	BioMed Central
Publisher Date	2024-08-28
Access Restriction	Open
Subject Keyword	Human Genetics Metabolomics Bioinformatics Medicine Public Health Cancer Research Systems Biology BRCA1 BRCA2 Copy number alterations Gene expression Synthetic viability CRISPR-Cas9 knockout TCGA ICGC DNA repair Medicine/Public Health
Content Type	Text
Resource Type	Article
Subject	Molecular Medicine Genetics Molecular Biology Genetics (clinical)
Journal Impact Factor	10.4/2023
5-Year Journal Impact Factor	12.6/2023

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1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
2	Indian Institute of Technology Kharagpur	Host Institute of the Project: The host institute of the project is responsible for providing infrastructure support and hosting the project	https://www.iitkgp.ac.in
3	National Digital Library of India Office, Indian Institute of Technology Kharagpur	The administrative and infrastructural headquarters of the project	Dr. B. Sutradhar bsutra@ndl.gov.in
4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
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