Large-scale phenogenomic analysis of human cancers uncovers frequent alterations affecting SMC5/6 complex components in breast cancer.

NAR Cancer Pub Date : 2023-09-11 eCollection Date: 2023-09-01 DOI:10.1093/narcan/zcad047
Shamayita Roy, Arvin Zaker, Arvind Mer, Damien D'Amours
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Abstract

Cancer cells often experience large-scale alterations in genome architecture because of DNA damage and replication stress. Whether mutations in core regulators of chromosome structure can also lead to cancer-promoting loss in genome stability is not fully understood. To address this question, we conducted a systematic analysis of mutations affecting a global regulator of chromosome biology -the SMC5/6 complex- in cancer genomics cohorts. Analysis of 64 959 cancer samples spanning 144 tissue types and 199 different cancer genome studies revealed that the SMC5/6 complex is frequently altered in breast cancer patients. Patient-derived mutations targeting this complex associate with strong phenotypic outcomes such as loss of ploidy control and reduced overall survival. Remarkably, the phenotypic impact of several patient mutations can be observed in a heterozygous context, hence providing an explanation for a prominent role of SMC5/6 mutations in breast cancer pathogenesis. Overall, our findings suggest that genes encoding global effectors of chromosome architecture can act as key contributors to cancer development in humans.

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对人类癌症的大规模表型基因组分析发现了乳腺癌中影响 SMC5/6 复合物成分的频繁改变。
由于 DNA 损伤和复制压力,癌细胞的基因组结构往往会发生大规模改变。染色体结构核心调控因子的突变是否也会导致基因组稳定性的丧失,目前尚不完全清楚。为了解决这个问题,我们在癌症基因组学队列中对影响染色体生物学全球调控因子--SMC5/6复合物--的突变进行了系统分析。我们对 64 959 份癌症样本进行了分析,涵盖 144 种组织类型和 199 项不同的癌症基因组研究,结果发现乳腺癌患者体内的 SMC5/6 复合物经常发生变化。以该复合体为靶点的患者基因突变会导致严重的表型结果,如倍性控制丧失和总生存率降低。值得注意的是,一些患者突变的表型影响可以在杂合的情况下观察到,从而为 SMC5/6 基因突变在乳腺癌发病机制中的突出作用提供了解释。总之,我们的研究结果表明,编码染色体结构全局效应因子的基因可能是导致人类癌症发生的关键因素。
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Pan-cancer analysis of promoter activity quantitative trait loci Large-scale phenogenomic analysis of human cancers uncovers frequent alterations affecting SMC5/6 complex components in breast cancer. Inhibition of nonsense-mediated mRNA decay reduces the tumorigenicity of human fibrosarcoma cells. CDK2 regulates collapsed replication fork repair in CCNE1-amplified ovarian cancer cells via homologous recombination. Editorial: DNA repair and nucleic acid therapeutics in cancer.
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