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The compensatory mechanisms enabling tumor growth in bBRCA1/2 contexts are unclear. This study identifies recurrent, large-scale copy number alterations enriched in human bBRCA1/2 tumors and validates their impact on proliferation using cellular models, integrating TCGA/ICGC analyses with genome-wide CRISPR/Cas9 screens and in vitro functional assays.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":40,"@type":76,"position":81},"https://docshare.wps.com/document/research-report/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/large-scale-copy-number-alterations-are-enriched-for-synthetic-viability-in-brca1brca2-tumors/332383/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/large-scale-copy-number-alterations-are-enriched-for-synthetic-viability-in-brca1brca2-tumors/332383.png","ImageObject",300,407,{"name":92,"@type":93},"Ezra","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-23","2026-09-21",true,{"@type":102,"interactionType":103,"userInteractionCount":52},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What question does the study address about BRCA1/BRCA2 loss?","Question",{"text":112,"@type":113},"It addresses how tumors with bi-allelic BRCA1/BRCA2 inactivation (bBRCA1/2), which is typically lethal and suppresses proliferation, manage to support oncogenic growth.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How were enriched copy number alterations identified in bBRCA1/2 tumors?",{"text":117,"@type":113},"The study compared copy number alterations in bBRCA1/2 breast and ovarian cancers from TCGA and ICGC against control tumors lacking evidence of homologous recombination deficiency, using Fisher’s exact test to find CNAs enriched in bBRCA1/2 tumors.",{"name":119,"@type":110,"acceptedAnswer":120},"What experimental approaches validated candidate genes and their effects?",{"text":121,"@type":113},"Genes in enriched CNA regions were screened by gene expression and tested for proliferation effects in genome-wide CRISPR/Cas9 screens, followed by in vitro clonogenic survival and functional assays to validate candidate genes.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},332383,1790507924,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":52,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145,"preview_page_count":4},1099514068035,"https://ap-avatar.wpscdn.com/davatar_276721f389ce27ea32af1340a28f341c","Zhu et al. Genome Medicine (2024) 16:108 [https://doi.org/10.1186/s13073-024-01371-y](https://doi.org/10.1186/s13073-024-01371-y)  \nGenome Medicine  \n RESEARCH Open Access  \nLarge-scale copy number alterations are  \nenriched for synthetic viability in BRCA1/BRCA2 tumors  \nYingjie Zhu1,2†, Xin Pei2†, Ardijana Novaj2, Jeremy Setton2, Daniel Bronder3, Fatemeh Derakhshan 1,4, Pier Selenica1, Niamh McDermott2, Mehmet Orman2, Sarina Plum3, Shyamal Subramanyan2,  \nSara H. Braverman2, Biko McMillan2, Sonali Sinha2, Jennifer Ma2, Andrea Gazzo1, Atif Khan2, Samuel Bakhoum2,3, Simon N. Powell2, Jorge S. Reis‑Filho 1* and Nadeem Riaz2*  \nAbstract  \nBackground 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.  \nMethods 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 set‑ ting of bBRCA1/2 mutations.  \nResults We found that bBRCA1/2 tumors harbor recurrent large‑scale genomic deletions significantly more fre‑ quently 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‑Inter‑ acting protein) . We identified loss of RIC8A, which occurs frequently in both bBRCA1/2 tumors and is synthetically via‑ ble 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  \n†Yingjie Zhu and Xin Pei contributed equally to this works.  \n*Correspondence: Jorge S. Reis‑Filho [jsreis@hotmail.com](jsreis@hotmail.com)[ ](jsreis@hotmail.com)Nadeem Riaz [riazn@mskcc.org](riazn@mskcc.org)  \nFull list of author information is available at the end of the article  \n© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit [http://creativecommons.org/licenses/by/4.0/](http://creativecommons.org/licenses/by/4.0/.)[.](http://creativecommons.org/licenses/by/4.0/.)  \nZhu et al. Genome Medicin","cbCaigL4TD4dI7qo","https://ap.wps.com/l/cbCaigL4TD4dI7qo","pdf",3924462,17,"English","# Abstract\n# Background\n# Methods\n# Results\n# Conclusions\n# Keywords","[{\"question\":\"What question does the study address about BRCA1/BRCA2 loss?\",\"answer\":\"It addresses how tumors with bi-allelic BRCA1/BRCA2 inactivation (bBRCA1/2), which is typically lethal and suppresses proliferation, manage to support oncogenic growth.\"},{\"question\":\"How were enriched copy number alterations identified in bBRCA1/2 tumors?\",\"answer\":\"The study compared copy number alterations in bBRCA1/2 breast and ovarian cancers from TCGA and ICGC against control tumors lacking evidence of homologous recombination deficiency, using Fisher’s exact test to find CNAs enriched in bBRCA1/2 tumors.\"},{\"question\":\"What experimental approaches validated candidate genes and their effects?\",\"answer\":\"Genes in enriched CNA regions were screened by gene expression and tested for proliferation effects in genome-wide CRISPR/Cas9 screens, followed by in vitro clonogenic survival and functional assays to validate candidate genes.\"}]","Large-scale copy number alterations are enriched for synthetic viability in BRCA1/BRCA2 tumors | PDF",1789997923,43]