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

Humans DNA Copy Number Variations BRCA2 Protein / genetics BRCA1 Protein / genetics Female Breast Neoplasms / genetics Ovarian Neoplasms / genetics Cell Proliferation Cell Line, Tumor Mutation Synthetic Lethal Mutations

BRCA1 BRCA2 CRISPR-Cas9 knockout Copy number alterations DNA repair Gene expression ICGC Synthetic viability TCGA

Journal

Genome medicine

ISSN: 1756-994X

Titre abrégé: Genome Med

Pays: England

ID NLM: 101475844

Informations de publication

Date de publication:
28 Aug 2024

Historique:

received: 29 10 2023

accepted: 02 08 2024

medline: 31 8 2024

pubmed: 31 8 2024

entrez: 28 8 2024

Statut: epublish

Résumé

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. 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. 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. 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.

Sections du résumé

BACKGROUND BACKGROUND

METHODS 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 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 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.

Identifiants

DOI: 10.1186/s13073-024-01371-y PMID: 39198848

pubmed: 39198848

doi: 10.1186/s13073-024-01371-y

pii: 10.1186/s13073-024-01371-y

doi:

Substances chimiques

BRCA2 Protein 0

BRCA1 Protein 0

BRCA1 protein, human 0

BRCA2 protein, human 0

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

Pagination

108

Subventions

Organisme : National Institutes of Health, National Cancer Institute

ID : P50CA247749

Organisme : Cancer Institute Cancer Center

ID : P30 CA008

Informations de copyright

Références

Maxwell KN, Wubbenhorst B, Wenz BM, Sloover DD, Pluta J, Emery L, et al. BRCA locus-specific loss of heterozygosity in germline BRCA1 and BRCA2 carriers. Nat Commun. 2017;8(1):319.

pubmed: 28831036 pmcid: 5567274 doi: 10.1038/s41467-017-00388-9

Group TAOCS, Patch A-M, Christie EL, Etemadmoghadam D, Garsed DW, George J, et al. Whole–genome characterization of chemoresistant ovarian cancer. Nature. 2015;521(7553):489–94.

doi: 10.1038/nature14410

Park W, Sokol E, Chen J, Yu KH, Khalil D, Harding JJ, et al. Landscape of DNA-damage-repair/homologous recombination deficiency (DDR/HRD) in hepatopancreaticobiliary (HPB) cancers. J Clin Oncol. 2020;38(15_suppl):4620.

doi: 10.1200/JCO.2020.38.15_suppl.4620

Tang M, Pei G, Su D, Wang C, Feng X, Srivastava M, et al. Genome-wide CRISPR screens reveal cyclin C as synthetic survival target of BRCA2. Nucleic Acids Res. 2021;49(13):7476–91.

pubmed: 34197614 pmcid: 8287926 doi: 10.1093/nar/gkab540

Riaz N, Blecua P, Lim RS, Shen R, Higginson DS, Weinhold N, et al. Pan-cancer analysis of bi-allelic alterations in homologous recombination DNA repair genes. Nat Commun. 2017;8(1):857.

pubmed: 29021619 pmcid: 5636842 doi: 10.1038/s41467-017-00921-w

Davies H, Glodzik D, Morganella S, Yates LR, Staaf J, Zou X, et al. HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures. Nat Med. 2017;23(4):517–25.

pubmed: 28288110 pmcid: 5833945 doi: 10.1038/nm.4292

Hakem R, de la Pompa JL, Sirard C, Mo R, Woo M, Hakem A, et al. The tumor suppressor gene Brca1 is required for embryonic cellular proliferation in the mouse. Cell. 1996;85(7):1009–23.

pubmed: 8674108 doi: 10.1016/S0092-8674(00)81302-1

Sharan SK, Morimatsu M, Albrecht U, Lim DS, Regel E, Dinh C, et al. Embryonic lethality and radiation hypersensitivity mediated by Rad51 in mice lacking Brca2. Nature. 1997;386(6627):804–10.

pubmed: 9126738 doi: 10.1038/386804a0

Feng W, Jasin M. BRCA2 suppresses replication stress-induced mitotic and G1 abnormalities through homologous recombination. Nat Commun. 2017;8(1):525.

pubmed: 28904335 pmcid: 5597640 doi: 10.1038/s41467-017-00634-0

Hart T, Tong AHY, Chan K, Van Leeuwen J, Seetharaman A, Aregger M, et al. Evaluation and design of genome-wide CRISPR/SpCas9 knockout screens. G3 (Bethesda). 2017;7(8):2719–27.

pubmed: 28655737 doi: 10.1534/g3.117.041277

Blomen VA, Majek P, Jae LT, Bigenzahn JW, Nieuwenhuis J, Staring J, et al. Gene essentiality and synthetic lethality in haploid human cells. Science. 2015;350(6264):1092–6.

pubmed: 26472760 doi: 10.1126/science.aac7557

Gu Y, Wang R, Han Y, Zhou W, Zhao Z, Chen T, et al. A landscape of synthetic viable interactions in cancer. Brief Bioinform. 2018;19(4):644–55.

pubmed: 28096076

Bunting SF, Callen E, Wong N, Chen HT, Polato F, Gunn A, et al. 53BP1 inhibits homologous recombination in Brca1-deficient cells by blocking resection of DNA breaks. Cell. 2010;141(2):243–54.

pubmed: 20362325 pmcid: 2857570 doi: 10.1016/j.cell.2010.03.012

Bouwman P, Aly A, Escandell JM, Pieterse M, Bartkova J, van der Gulden H, et al. 53BP1 loss rescues BRCA1 deficiency and is associated with triple-negative and BRCA-mutated breast cancers. Nat Struct Mol Biol. 2010;17(6):688–95.

pubmed: 20453858 pmcid: 2912507 doi: 10.1038/nsmb.1831

Cressman VL, Backlund DC, Avrutskaya AV, Leadon SA, Godfrey V, Koller BH. Growth retardation, DNA repair defects, and lack of spermatogenesis in BRCA1-deficient mice. Mol Cell Biol. 1999;19(10):7061–75.

pubmed: 10490643 pmcid: 84701 doi: 10.1128/MCB.19.10.7061

Xu X, Qiao W, Linke SP, Cao L, Li WM, Furth PA, et al. Genetic interactions between tumor suppressors Brca1 and p53 in apoptosis, cell cycle and tumorigenesis. Nat Genet. 2001;28(3):266–71.

pubmed: 11431698 doi: 10.1038/90108

Brodie SG, Xu X, Qiao W, Li WM, Cao L, Deng CX. Multiple genetic changes are associated with mammary tumorigenesis in Brca1 conditional knockout mice. Oncogene. 2001;20(51):7514–23.

pubmed: 11709723 doi: 10.1038/sj.onc.1204929

Liu X, Holstege H, van der Gulden H, Treur-Mulder M, Zevenhoven J, Velds A, et al. Somatic loss of BRCA1 and p53 in mice induces mammary tumors with features of human BRCA1-mutated basal-like breast cancer. Proc Natl Acad Sci USA. 2007;104(29):12111–6.

pubmed: 17626182 pmcid: 1924557 doi: 10.1073/pnas.0702969104

Manie E, Vincent-Salomon A, Lehmann-Che J, Pierron G, Turpin E, Warcoin M, et al. High frequency of TP53 mutation in BRCA1 and sporadic basal-like carcinomas but not in BRCA1 luminal breast tumors. Cancer Res. 2009;69(2):663–71.

pubmed: 19147582 doi: 10.1158/0008-5472.CAN-08-1560

Hakem R, de la Pompa JL, Elia A, Potter J, Mak TW. Partial rescue of Brca1 (5–6) early embryonic lethality by p53 or p21 null mutation. Nat Genet. 1997;16(3):298–302.

pubmed: 9207798 doi: 10.1038/ng0797-298

Holstege H, Joosse SA, van Oostrom CT, Nederlof PM, de Vries A, Jonkers J. High incidence of protein-truncating TP53 mutations in BRCA1-related breast cancer. Cancer Res. 2009;69(8):3625–33.

pubmed: 19336573 doi: 10.1158/0008-5472.CAN-08-3426

Mavaddat N, Barrowdale D, Andrulis IL, Domchek SM, Eccles D, Nevanlinna H, et al. Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Cancer Epidemiol Biomarkers Prev. 2012;21(1):134–47.

pubmed: 22144499 doi: 10.1158/1055-9965.EPI-11-0775

Steele CD, Abbasi A, Islam SMA, Bowes AL, Khandekar A, Haase K, et al. Signatures of copy number alterations in human cancer. Nature. 2022;606(7916):984–91.

pubmed: 35705804 pmcid: 9242861 doi: 10.1038/s41586-022-04738-6

Solimini NL, Xu Q, Mermel CH, Liang AC, Schlabach MR, Luo J, et al. Recurrent hemizygous deletions in cancers may optimize proliferative potential. Science. 2012;337(6090):104–9.

pubmed: 22628553 pmcid: 4027969 doi: 10.1126/science.1219580

Davoli T, Xu AW, Mengwasser KE, Sack LM, Yoon JC, Park PJ, et al. Cumulative haploinsufficiency and triplosensitivity drive aneuploidy patterns and shape the cancer genome. Cell. 2013;155(4):948–62.

pubmed: 24183448 pmcid: 3891052 doi: 10.1016/j.cell.2013.10.011

Zack TI, Schumacher SE, Carter SL, Cherniack AD, Saksena G, Tabak B, et al. Pan-cancer patterns of somatic copy number alteration. Nat Genet. 2013;45(10):1134–40.

pubmed: 24071852 pmcid: 3966983 doi: 10.1038/ng.2760

Hoadley KA, Yau C, Hinoue T, Wolf DM, Lazar AJ, Drill E, et al. Cell-of-origin patterns dominate the molecular classification of 10,000 tumors from 33 types of cancer. Cell. 2018;173(2):291-304 e6.

pubmed: 29625048 pmcid: 5957518 doi: 10.1016/j.cell.2018.03.022

Ellrott K, Bailey MH, Saksena G, Covington KR, Kandoth C, Stewart C, et al. Scalable open science approach for mutation calling of tumor exomes using multiple genomic pipelines. Cell Syst. 2018;6(3):271-81 e7.

pubmed: 29596782 pmcid: 6075717 doi: 10.1016/j.cels.2018.03.002

Consortium ITP-CAoWG. Pan-cancer analysis of whole genomes. Nature. 2020;578(7793):82–93.

doi: 10.1038/s41586-020-1969-6

Shen R, Seshan VE. FACETS: allele-specific copy number and clonal heterogeneity analysis tool for high-throughput DNA sequencing. Nucleic Acids Res. 2016;44(16): e131.

pubmed: 27270079 pmcid: 5027494 doi: 10.1093/nar/gkw520

Hunt SE, Moore B, Amode RM, Armean IM, Lemos D, Mushtaq A, et al. Annotating and prioritizing genomic variants using the ensembl variant effect predictor-a tutorial. Hum Mutat. 2022;43(8):986–97.

pubmed: 34816521 doi: 10.1002/humu.24298

Quinlan AR, Hall IM. BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics. 2010;26(6):841–2.

pubmed: 20110278 pmcid: 2832824 doi: 10.1093/bioinformatics/btq033

Riaz N, Havel JJ, Kendall SM, Makarov V, Walsh LA, Desrichard A, et al. Recurrent SERPINB3 and SERPINB4 mutations in patients who respond to anti-CTLA4 immunotherapy. Nat Genet. 2016;48(11):1327–9.

pubmed: 27668655 pmcid: 5553281 doi: 10.1038/ng.3677

Kim J, Mouw KW, Polak P, Braunstein LZ, Kamburov A, Tiao G, et al. Somatic ERCC2 mutations are associated with a distinct genomic signature in urothelial tumors. Nat Genet. 2016;48(6):600–6.

pubmed: 27111033 pmcid: 4936490 doi: 10.1038/ng.3557

Gotelli NJ, Ellison AM. EcoSimR 1.00. 2013. Available from: http://www.uvm.edu/~ngotelli/EcoSim/EcoSim.html .

Sondka Z, Bamford S, Cole CG, Ward SA, Dunham I, Forbes SA. The COSMIC cancer gene census: describing genetic dysfunction across all human cancers. Nat Rev Cancer. 2018;18(11):696–705.

pubmed: 30293088 pmcid: 6450507 doi: 10.1038/s41568-018-0060-1

Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15(12):550.

pubmed: 25516281 pmcid: 4302049 doi: 10.1186/s13059-014-0550-8

Chu T, Wang Z, Pe’er D, Danko CG. Cell type and gene expression deconvolution with BayesPrism enables Bayesian integrative analysis across bulk and single-cell RNA sequencing in oncology. Nat Cancer. 2022;3(4):505–17.

pubmed: 35469013 pmcid: 9046084 doi: 10.1038/s43018-022-00356-3

Uhlen M, Fagerberg L, Hallstrom BM, Lindskog C, Oksvold P, Mardinoglu A, et al. Proteomics. Tissue-based map of the human proteome. Science. 2015;347(6220):1260419.

pubmed: 25613900 doi: 10.1126/science.1260419

Li W, Xu H, Xiao T, Cong L, Love MI, Zhang F, et al. MAGeCK enables robust identification of essential genes from genome-scale CRISPR/Cas9 knockout screens. Genome Biol. 2014;15(12):554.

pubmed: 25476604 pmcid: 4290824 doi: 10.1186/s13059-014-0554-4

Kim E, Hart T. Improved analysis of CRISPR fitness screens and reduced off-target effects with the BAGEL2 gene essentiality classifier. Genome Med. 2021;13(1):2.

pubmed: 33407829 pmcid: 7789424 doi: 10.1186/s13073-020-00809-3

Alvarez-Quilon A, Wojtaszek JL, Mathieu MC, Patel T, Appel CD, Hustedt N, et al. Endogenous DNA 3’ blocks are vulnerabilities for BRCA1 and BRCA2 deficiency and are reversed by the APE2 nuclease. Mol Cell. 2020;78(6):1152-65 e8.

pubmed: 32516598 pmcid: 7340272 doi: 10.1016/j.molcel.2020.05.021

Zimmermann M, Murina O, Reijns MAM, Agathanggelou A, Challis R, Tarnauskaite Z, et al. CRISPR screens identify genomic ribonucleotides as a source of PARP-trapping lesions. Nature. 2018;559(7713):285–9.

pubmed: 29973717 pmcid: 6071917 doi: 10.1038/s41586-018-0291-z

Hart T, Moffat J. BAGEL: a computational framework for identifying essential genes from pooled library screens. BMC Bioinform. 2016;17:164.

doi: 10.1186/s12859-016-1015-8

Meyers RM, Bryan JG, McFarland JM, Weir BA, Sizemore AE, Xu H, et al. Computational correction of copy number effect improves specificity of CRISPR-Cas9 essentiality screens in cancer cells. Nat Genet. 2017;49(12):1779–84.

pubmed: 29083409 pmcid: 5709193 doi: 10.1038/ng.3984

Jassal B, Matthews L, Viteri G, Gong C, Lorente P, Fabregat A, et al. The reactome pathway knowledgebase. Nucleic Acids Res. 2020;48(D1):D498–503.

pubmed: 31691815

Raudvere U, Kolberg L, Kuzmin I, Arak T, Adler P, Peterson H, et al. g:Profiler: a web server for functional enrichment analysis and conversions of gene lists (2019 update). Nucleic Acids Res. 2019;47(W1):W191–8.

pubmed: 31066453 pmcid: 6602461 doi: 10.1093/nar/gkz369

Schmidt L, Wiedner M, Velimezi G, Prochazkova J, Owusu M, Bauer S, et al. ATMIN is required for the ATM-mediated signaling and recruitment of 53BP1 to DNA damage sites upon replication stress. DNA Repair (Amst). 2014;24:122–30.

pubmed: 25262557 doi: 10.1016/j.dnarep.2014.09.001

Cuaron JJ, Chang C, Lovelock M, Higginson DS, Mah D, Cahlon O, et al. Exponential Increase in relative biological effectiveness along distal edge of a proton Bragg peak as measured by deoxyribonucleic acid double-strand breaks. Int J Radiat Oncol Biol Phys. 2016;95(1):62–9.

pubmed: 27084629 pmcid: 5005074 doi: 10.1016/j.ijrobp.2016.02.018

Eccles LJ, Bell AC, Powell SN. Inhibition of non-homologous end joining in Fanconi Anemia cells results in rescue of survival after interstrand crosslinks but sensitization to replication associated double-strand breaks. DNA Repair (Amst). 2018;64:1–9.

pubmed: 29459202 doi: 10.1016/j.dnarep.2018.02.003

Bertucci F, Ng CKY, Patsouris A, Droin N, Piscuoglio S, Carbuccia N, et al. Genomic characterization of metastatic breast cancers. Nature. 2019;569(7757):560–4.

pubmed: 31118521 doi: 10.1038/s41586-019-1056-z

Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV, et al. Signatures of mutational processes in human cancer. Nature. 2013;500(7463):415–21.

pubmed: 23945592 pmcid: 3776390 doi: 10.1038/nature12477

Bouwman P, Aly A, Escandell JM, Pieterse M, Bartkova J, Gulden Hvd, et al. 53BP1 loss rescues BRCA1 deficiency and is associated with triple-negative and BRCA-mutated breast cancers. Nat Struct Mol Biol. 2010;17(6):688–95.

pubmed: 20453858 pmcid: 2912507 doi: 10.1038/nsmb.1831

Ray Chaudhuri A, Callen E, Ding X, Gogola E, Duarte AA, Lee JE, et al. Replication fork stability confers chemoresistance in BRCA-deficient cells. Nature. 2016;535(7612):382–7.

pubmed: 27443740 doi: 10.1038/nature18325

Grushko TA, Dignam JJ, Das S, Blackwood AM, Perou CM, Ridderstrale KK, et al. MYC is amplified in BRCA1-associated breast cancers. Clin Cancer Res. 2004;10(2):499–507.

pubmed: 14760071 doi: 10.1158/1078-0432.CCR-0976-03

Group PTC, Calabrese C, Davidson NR, Demircioglu D, Fonseca NA, He Y, et al. Genomic basis for RNA alterations in cancer. Nature. 2020;578(7793):129–36.

doi: 10.1038/s41586-020-1970-0

Shao X, Lv N, Liao J, Long J, Xue R, Ai N, et al. Copy number variation is highly correlated with differential gene expression: a pan-cancer study. BMC Med Genet. 2019;20(1):175.

pubmed: 31706287 pmcid: 6842483 doi: 10.1186/s12881-019-0909-5

Ding X, Ray Chaudhuri A, Callen E, Pang Y, Biswas K, Klarmann KD, et al. Synthetic viability by BRCA2 and PARP1/ARTD1 deficiencies. Nat Commun. 2016;7:12425.

pubmed: 27498558 pmcid: 4979061 doi: 10.1038/ncomms12425

Thomas LW, Esposito C, Morgan RE, Price S, Young J, Williams SP, et al. Genome-wide CRISPR/Cas9 deletion screen defines mitochondrial gene essentiality and identifies routes for tumour cell viability in hypoxia. Commun Biol. 2021;4(1):615.

pubmed: 34021238 pmcid: 8140129 doi: 10.1038/s42003-021-02098-x

Lord CJ, Ashworth A. PARP inhibitors: synthetic lethality in the clinic. Science. 2017;355(6330):1152–8.

pubmed: 28302823 pmcid: 6175050 doi: 10.1126/science.aam7344

Mengwasser KE, Adeyemi RO, Leng Y, Choi MY, Clairmont C, D’Andrea AD, et al. Genetic screens reveal FEN1 and APEX2 as BRCA2 synthetic lethal targets. Mol Cell. 2019;73(5):885-99 e6.

pubmed: 30686591 pmcid: 6892393 doi: 10.1016/j.molcel.2018.12.008

Guo E, Ishii Y, Mueller J, Srivatsan A, Gahman T, Putnam CD, et al. FEN1 endonuclease as a therapeutic target for human cancers with defects in homologous recombination. Proc Natl Acad Sci U S A. 2020;117(32):19415–24.

pubmed: 32719125 pmcid: 7431096 doi: 10.1073/pnas.2009237117

He YJ, Meghani K, Caron MC, Yang C, Ronato DA, Bian J, et al. DYNLL1 binds to MRE11 to limit DNA end resection in BRCA1-deficient cells. Nature. 2018;563(7732):522–6.

pubmed: 30464262 pmcid: 7155769 doi: 10.1038/s41586-018-0670-5

Gabay M, Pinter ME, Wright FA, Chan P, Murphy AJ, Valenzuela DM, et al. Ric-8 proteins are molecular chaperones that direct nascent G protein alpha subunit membrane association. Sci Signal. 2011;4(200):ra79.

pubmed: 22114146 doi: 10.1126/scisignal.2002223

Chan P, Thomas CJ, Sprang SR, Tall GG. Molecular chaperoning function of Ric-8 is to fold nascent heterotrimeric G protein alpha subunits. Proc Natl Acad Sci U S A. 2013;110(10):3794–9.

pubmed: 23431197 pmcid: 3593926 doi: 10.1073/pnas.1220943110

Chishiki K, Kamakura S, Yuzawa S, Hayase J, Sumimoto H. Ubiquitination of the heterotrimeric G protein alpha subunits Galphai2 and Galphaq is prevented by the guanine nucleotide exchange factor Ric-8A. Biochem Biophys Res Commun. 2013;435(3):414–9.

pubmed: 23665327 doi: 10.1016/j.bbrc.2013.04.103

Shih J, Sarmashghi S, Zhakula-Kostadinova N, Zhang S, Georgis Y, Hoyt SH, et al. Cancer aneuploidies are shaped primarily by effects on tumour fitness. Nature. 2023;619:793.

pubmed: 37380777 pmcid: 10529820 doi: 10.1038/s41586-023-06266-3

Mermel CH, Schumacher SE, Hill B, Meyerson ML, Beroukhim R, Getz G. GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers. Genome Biol. 2011;12(4):R41.

pubmed: 21527027 pmcid: 3218867 doi: 10.1186/gb-2011-12-4-r41

Wang L, Guo D, Xing B, Zhang JJ, Shu HB, Guo L, et al. Resistance to inhibitors of cholinesterase-8A (Ric-8A) is critical for growth factor receptor-induced actin cytoskeletal reorganization. J Biol Chem. 2011;286(35):31055–61.

pubmed: 21771786 pmcid: 3162464 doi: 10.1074/jbc.M111.253427

Chan P, Gabay M, Wright FA, Kan W, Oner SS, Lanier SM, et al. Purification of heterotrimeric G protein alpha subunits by GST-Ric-8 association: primary characterization of purified G alpha(olf). J Biol Chem. 2011;286(4):2625–35.

pubmed: 21115479 doi: 10.1074/jbc.M110.178897

Wu V, Yeerna H, Nohata N, Chiou J, Harismendy O, Raimondi F, et al. Illuminating the Onco-GPCRome: novel G protein-coupled receptor-driven oncocrine networks and targets for cancer immunotherapy. J Biol Chem. 2019;294(29):11062–86.

pubmed: 31171722 pmcid: 6643028 doi: 10.1074/jbc.REV119.005601

Karnik P, Paris M, Williams BR, Casey G, Crowe J, Chen P. Two distinct tumor suppressor loci within chromosome 11p15 implicated in breast cancer progression and metastasis. Hum Mol Genet. 1998;7(5):895–903.

pubmed: 9536095 doi: 10.1093/hmg/7.5.895

Tonissoo T, Lulla S, Meier R, Saare M, Ruisu K, Pooga M, et al. Nucleotide exchange factor RIC-8 is indispensable in mammalian early development. Dev Dyn. 2010;239(12):3404–15.

pubmed: 21069829 doi: 10.1002/dvdy.22480

Nichols CA, Gibson WJ, Brown MS, Kosmicki JA, Busanovich JP, Wei H, et al. Loss of heterozygosity of essential genes represents a widespread class of potential cancer vulnerabilities. Nat Commun. 2020;11(1):2517.

pubmed: 32433464 pmcid: 7239950 doi: 10.1038/s41467-020-16399-y

Ellrott K, Bailey MH, Saksena G, Covington KR, Kandoth C, Stewart C, et al. PanCancerAtlas MC3. TCGA. 2018; Available from: https://gdc.cancer.gov/about-data/publications/mc3-2017 .

Hoadley KA, Yau C, Hinoue T, Wolf DM, Lazar AJ, Drill E, et al. Gene expression. TCGA. 2018;Available from: https://portal.gdc.cancer.gov .

Zhu Y, Pei X. Large-scale copy number alterations are enriched for synthetic viability in BRCA1/BRCA2 tumors. SRA. 2024; Available from: https://www.ncbi.nlm.nih.gov/bioproject/?term=PRJNA1096436 .

Zhu Y, Pei X. BRCA-CN. GitHub. 2024. Available from: https://github.com/Yingjie848/BRCA-CN .