Detection of Molecular Signatures of Homologous Recombination Deficiency in Bladder Cancer.
Detection of Molecular Signatures of Homologous Recombination Deficiency in Bladder Cancer.
复制标题
DOI：
10.1158/1078-0432.ccr-20-5037
复制
发表时间：
2021-07-01
期刊：
影响因子：
--
通讯作者：
Szallasi Z
中科院分区：
文献类型：
--
作者：
Börcsök J;Diossy M;Sztupinszki Z;Prosz A;Tisza V;Spisak S;Rusz O;Stormoen DR;Pappot H;Csabai I;Brunak S;Mouw KW;Szallasi Z
PARP抑制剂被批准用于乳腺癌、卵巢癌、前列腺癌和胰腺癌，这些肿瘤是最常发生关键同源重组(HR)基因改变的实体肿瘤类型，如BRCA1/2。然而，包括膀胱癌在内的其他实体肿瘤类型中HR缺陷的频率尚未得到很好的描述。同源重组缺陷(HRD)可诱导特定的DNA异常特征(突变特征)，即使在没有观察到HR基因改变的情况下，这些“基因组疤痕”的存在也可用于评估给定肿瘤活检中HR缺陷的存在或不存在。利用全外显子组和全基因组数据，我们测量了膀胱癌中与HR缺乏相关的各种突变特征。我们发现，膀胱肿瘤的一部分有HR缺乏的证据。除了少数具有双等位基因BRCA1/2事件的肿瘤外，大约10%的膀胱肿瘤有明显的HR缺乏相关突变特征的证据。HRD签名水平的增加与RBBP8的启动子甲基化有关，RBBP8编码CtIP，CtIP是参与HR的关键蛋白。一组膀胱肿瘤具有提示HR缺乏的基因组特征，因此可能更有可能从针对肿瘤HR缺乏的铂类药物和PARP抑制剂等治疗中受益。
PARP inhibitors are approved for use in breast, ovarian, prostate and pancreatic cancer, which are the solid tumor types that most frequently have alterations in key homologous recombination (HR) genes, such as BRCA1/2. However, the frequency of HR deficiency in other solid tumor types, including bladder cancer, is less well characterized. Specific DNA aberration profiles (mutational signatures) are induced by homologous recombination deficiency (HRD) and the presence of these “genomic scars” can be used to assess the presence or absence of HR deficiency in a given tumor biopsy even in the absence of an observed alteration of an HR gene. Using whole exome and whole genome data, we measured various HR deficiency-associated mutational signatures in bladder cancer. We found that a subset of bladder tumors have evidence of HR deficiency. In addition to a small number of tumors with bi-allelic BRCA1/2 events, approximately 10% of bladder tumors had significant evidence of HR deficiency associated mutational signatures. Increased levels of HRD signatures were associated with promoter methylation of RBBP8 which encodes CtIP, a key protein involved in HR. A subset of bladder tumors have genomic features suggestive of HR deficiency and therefore may be more likely to benefit from therapies such as platinum agents and PARP inhibitors that target tumor HR deficiency.