Detection of Molecular Signatures of Homologous Recombination Deficiency in Prostate Cancer with or without BRCA1/2 Mutations.
Detection of Molecular Signatures of Homologous Recombination Deficiency in Prostate Cancer with or without BRCA1/2 Mutations.
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DOI：
10.1158/1078-0432.ccr-19-2135
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发表时间：
2020-06-01
期刊：
影响因子：
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通讯作者：
Szallasi Z
中科院分区：
文献类型：
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作者：
Sztupinszki Z;Diossy M;Krzystanek M;Borcsok J;Pomerantz MM;Tisza V;Spisak S;Rusz O;Csabai I;Freedman ML;Szallasi Z
同源重组（HR）相关基因突变的前列腺癌，最常见的是BRCA 2，对PARP抑制和铂类化疗反应良好。我们研究了在这些特定基因中没有有害突变的其他前列腺肿瘤是否同样缺乏HR，可能使那些对HR导向治疗敏感。HRD水平可以使用衍生自下一代测序数据的各种突变特征来估计。我们使用这种方法对原发性和转移性前列腺癌（PRAD）的全基因组（n=311）和全外显子组测序数据（n=498），以确定前列腺癌病例是否在体细胞肿瘤活检中显示出HRD的明确体征。已知的BRCA缺陷样本在全基因组测序数据中显示了所有先前描述的HR缺陷相关突变特征。在BRCA 1/2或其他HR相关基因中未携带生殖系或体细胞突变的患者亚组中也检测到HRD相关突变特征。从全外显子组测序数据中也获得了类似的结果，尽管灵敏度和准确度较低。这些发现可能会增加可能对PARP抑制剂治疗有反应的病例数量。基于HR相关突变特征，5- 8%的局限性前列腺癌病例可能是PARP抑制剂治疗的良好候选者（包括具有BRCA 1/2突变的那些）。
Prostate cancers with mutations in genes involved in homologous recombination (HR), most commonly BRCA2, respond favorably to PARP inhibition and platinum-based chemotherapy. We investigated whether other prostate tumors that do not harbor deleterious mutations in these particular genes can similarly be deficient in HR, likely rendering those sensitive to HR-directed therapies. HRD levels can be estimated using various mutational signatures derived from next-generation sequencing data. We used this approach on whole genome (n=311) and whole exome sequencing data (n=498) of both primary and metastatic prostate adenocarcinomas (PRAD) to determine whether prostate cancer cases display clear signs of HRD in somatic tumor biopsies. Known BRCA-deficient samples showed all previously described HR-deficiency associated mutational signatures in the whole genome sequencing data. HRD-associated mutational signatures were also detected in a subset of patients who did not harbor germline or somatic mutations in BRCA1/2 or other HR-related genes. Similar results, albeit with lower sensitivity and accuracy, were also obtained from whole exome sequencing data. These findings may expand the number of cases likely to respond to PARP inhibitor treatment. Based on the HR-associated mutational signatures, 5-8 % of localized prostate cancer cases may be good candidates for PARP-inhibitor treatment (including those with BRCA1/2 mutations).