ArticleGenome medicine2024
Large-scale copy number alterations are enriched for synthetic viability in BRCA1/BRCA2 tumors.
Article in Genome medicine, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed.
- DISCERN: inferring drug sensitivity from single-cell transcriptomes using cell-type-specific genetic interaction networks.Genome medicine · 2026Article
- Gene Expression Profiling to Unveil Novel Biomarkers for Early Diagnosis and Therapies for Breast Cancer.Current topics in medicinal chemistry · 2026Article
- Contrasting roles of APE1 and APE2 in genome maintenance, cancer development, and therapeutic targeting.NAR cancer · 2025Review
- The cold immunological landscape of ATM-deficient cancers.Journal for immunotherapy of cancer · 2025Article
- Comprehensive analysis of molecular characteristics between primary and breast-derived metastatic ovarian cancer.Translational cancer research · 2025Article
- Large-scale copy number alterations are enriched for synthetic viability in BRCA1/BRCA2 tumors.Genome medicine · 2024Article
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21 authors.
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Abstract
backgroundPathogenic 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.
methodsWe 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.
resultsWe 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.
conclusionsThis 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.
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