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

IF 10.4 1区 生物学 Q1 GENETICS & HEREDITY Genome Medicine Pub Date : 2024-08-28 DOI:10.1186/s13073-024-01371-y
Yingjie Zhu, Xin Pei, Ardijana Novaj, Jeremy Setton, Daniel Bronder, Fatemeh Derakhshan, Pier Selenica, Niamh McDermott, Mehmet Orman, Sarina Plum, Shyamal Subramanyan, Sara H Braverman, Biko McMillan, Sonali Sinha, Jennifer Ma, Andrea Gazzo, Atif Khan, Samuel Bakhoum, Simon N Powell, Jorge S Reis-Filho, Nadeem Riaz
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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.

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在 BRCA1/BRCA2 肿瘤中,大规模拷贝数改变富含合成活力。
背景:致病性 BRCA1 或 BRCA2 基因突变会导致遗传性乳腺癌、卵巢癌、前列腺癌和胰腺癌。矛盾的是,BRCA1 或 BRCA2 的双等位基因失活(bBRCA1/2)会导致胚胎死亡并减少细胞增殖。促进 bBRCA1/2 肿瘤发生癌变的代偿机制仍不清楚:方法:我们确定了人类 bBRCA1/2 肿瘤中富集的复发性基因改变,并通过实验验证了这些改变是否能改善细胞模型的增殖。我们分析了TCGA和ICGC中bBRCA1/2乳腺癌和卵巢癌的突变和拷贝数改变(CNA)。与缺乏同源重组缺陷证据的对照组肿瘤相比,我们使用费雪精确检验来确定 bBRCA1/2 肿瘤中富集的 CNA。在全基因组CRISPR/Cas9筛选中,我们通过基因表达及其对增殖的影响进一步筛选了位于bBRCA1/2肿瘤中富集的CNA区域的基因。一组候选基因通过体外克隆生成存活和功能试验进行了功能验证,以验证它们在 bBRCA1/2 基因突变的情况下对增殖的影响:结果:我们发现,bBRCA1/2肿瘤复发性大规模基因组缺失的频率明显高于组织学匹配的对照组(乳腺癌和卵巢癌中的细胞带数为238个)。在缺失区域内,我们发现了 277 个 BRCA1 相关基因和 218 个 BRCA2 相关基因,在全基因组 CRISPR 筛选中,这些基因在 bBRCA1/2 细胞中表达减少,增殖增加,而在野生型细胞中则没有。通过克隆增殖试验对 20 个候选基因进行体外验证,结果验证了 9 个基因,包括 RIC8A 和 ATMIN(ATM-Interacting protein)。我们发现了 RIC8A 的缺失,它在 bBRCA1/2 肿瘤中经常出现,并且在 BRCA1 和 BRCA2 缺失的情况下也能合成。此外,我们发现转移性同源重组缺陷癌症会获得 RIC8A 的功能缺失突变。最后,我们发现RIC8A不能挽救同源重组缺陷,但可能会影响bBRCA1/2肿瘤的有丝分裂,从而可能导致微核形成增加:本研究为解决肿瘤抑制剂悖论提供了一种方法,即鉴定合成的活力相互作用和受人类癌症中大规模 CNA 影响的因果驱动基因。
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来源期刊
Genome Medicine
Genome Medicine GENETICS & HEREDITY-
CiteScore
20.80
自引率
0.80%
发文量
128
审稿时长
6-12 weeks
期刊介绍: Genome Medicine is an open access journal that publishes outstanding research applying genetics, genomics, and multi-omics to understand, diagnose, and treat disease. Bridging basic science and clinical research, it covers areas such as cancer genomics, immuno-oncology, immunogenomics, infectious disease, microbiome, neurogenomics, systems medicine, clinical genomics, gene therapies, precision medicine, and clinical trials. The journal publishes original research, methods, software, and reviews to serve authors and promote broad interest and importance in the field.
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