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首页> 外文期刊>Cancer research: The official organ of the American Association for Cancer Research, Inc >Ovarian Cancers Harboring Inactivating Mutations in CDK12 Display a Distinct Genomic Instability Pattern Characterized by Large Tandem Duplications
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Ovarian Cancers Harboring Inactivating Mutations in CDK12 Display a Distinct Genomic Instability Pattern Characterized by Large Tandem Duplications

机译：携带CDK12失活突变的卵巢癌显示以大串联重复为特征的独特基因组不稳定性模式

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摘要

CDK12 is a recurrently mutated gene in serous ovarian carcinoma, whose downregulation is associated with impaired expression of DNA damage repair genes and subsequent hypersensitivity to DNA-damaging agents and PARP1/2 inhibitors. In this study, we investigated the genomic landscape associated with CDK12 inactivation in patients with serous ovarian carcinoma. We show that CDK12 loss was consistently associated with a particular genomic instability pattern characterized by hundreds of tandem duplications of up to 10 megabases (Mb) in size. Tandem duplications were characterized by a bimodal (similar to 0.3 and similar to 3 Mb) size distribution and overlapping microhomology at the breakpoints. This genomic instability, denoted as the CDK12 TD-plus phenotype, is remarkably distinct from other alteration patterns described in breast and ovarian cancers. The CDK12 TD-plus phenotype was associated with a greater than 10% gain in genomic content and occurred at a 3% to 4% rate in The Cancer Genome Atlas-derived and in-house cohorts of patients with serous ovarian carcinoma. Moreover, CDK12-inactivating mutations together with the TD-plus phenotype were also observed in prostate cancers. Our finding provides new insight toward deciphering the function of CDK12 in genome maintenance and oncogenesis.
机译：CDK12是浆液性卵巢癌中的一个反复突变的基因，其下调与DNA损伤修复基因的表达受损以及随后对DNA损伤剂和PARP1 / 2抑制剂的超敏反应有关。在这项研究中，我们调查了浆液性卵巢癌患者与CDK12失活相关的基因组格局。我们表明，CDK12丢失与特定的基因组不稳定性模式一致，其特征是数百个串联重复，最大重复大小为10兆碱基（Mb）。串联重复的特征是双峰（类似于0.3且类似于3 Mb）的大小分布和在断点处的重叠微同源性。这种基因组的不稳定性，称为CDK12 TD-plus表型，与乳腺癌和卵巢癌中描述的其他改变方式明显不同。 CDK12 TD加表型与基因组含量增加超过10％有关，在浆液性卵巢癌患者的癌症基因组图谱来源和内部队列中，发生率为3％至4％。此外，在前列腺癌中也观察到CDK12失活突变和TD加表型。我们的发现为破译CDK12在基因组维持和肿瘤发生中的功能提供了新的见识。

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