Division of Surgical Oncology, Department of Surgery, College of Medicine, The University of Illinois at Chicago, 840 S. Wood Street, Suite 601 Clinical Sciences Building, Chicago, IL, 60612, USA.
Medical Scientist Training Program, University of Illinois College of Medicine, Chicago, IL, USA.
Sci Rep. 2020 Nov 19;10(1):20223. doi: 10.1038/s41598-020-76975-6.
PARP inhibitors have shown remarkable efficacy in the clinical management of several BRCA-mutated tumors. This approach is based on the long-standing hypothesis that PARP inhibition will impair the repair of single stranded breaks, causing synthetic lethality in tumors with loss of high-fidelity double-strand break homologous recombination. While this is now well accepted and has been the basis of several successful clinical trials, emerging evidence strongly suggests that mutation to several additional genes involved in homologous recombination may also have predictive value for PARP inhibitors. While this notion is supported by early clinical evidence, the mutation frequencies of these and other functionally related genes are largely unknown, particularly in cancers not classically associated with homologous recombination deficiency. We therefore evaluated the mutation status of 22 genes associated with the homologous recombination DNA repair pathway or PARP inhibitor sensitivity, first in a pan-cancer cohort of 55,586 patients, followed by a more focused analysis in The Cancer Genome Atlas cohort of 12,153 patients. In both groups we observed high rates of mutations in a variety of HR-associated genes largely unexplored in the setting of PARP inhibition, many of which were associated also with poor clinical outcomes. We then extended our study to determine which mutations have a known oncogenic role, as well as similar to known oncogenic mutations that may have a similar phenotype. Finally, we explored the individual cancer histologies in which these genomic alterations are most frequent. We concluded that the rates of deleterious mutations affecting genes associated with the homologous recombination pathway may be underrepresented in a wide range of human cancers, and several of these genes warrant further and more focused investigation, particularly in the setting of PARP inhibition and HR deficiency.
聚腺苷二磷酸核糖聚合酶（PARP）抑制剂在几种 BRCA 突变肿瘤的临床治疗中显示出显著疗效。这种方法基于长期以来的假设，即 PARP 抑制将损害单链断裂的修复，导致同源重组高保真双链断裂缺失的肿瘤产生合成致死。虽然这一点现在已经被广泛接受，并已成为几项成功临床试验的基础，但新出现的证据强烈表明，涉及同源重组的几个额外基因的突变也可能对 PARP 抑制剂具有预测价值。虽然这一概念得到了早期临床证据的支持，但这些和其他功能相关基因的突变频率在很大程度上是未知的，特别是在与同源重组缺陷无关的癌症中。因此，我们首先在一个包含 55586 名患者的泛癌队列中评估了与同源重组 DNA 修复途径或 PARP 抑制剂敏感性相关的 22 个基因的突变状态，然后在包含 12153 名患者的癌症基因组图谱（The Cancer Genome Atlas，TCGA）队列中进行了更集中的分析。在这两个组中，我们观察到了各种 HR 相关基因中的突变率很高，这些基因在 PARP 抑制背景下很大程度上尚未被探索，其中许多基因与不良临床结局也有关。然后，我们扩展了研究范围，以确定哪些突变具有已知的致癌作用，以及与已知致癌突变相似、可能具有相似表型的突变。最后，我们探讨了这些基因组改变最常见的个体癌症组织学。我们得出结论，在广泛的人类癌症中，与同源重组途径相关的基因的有害突变率可能被低估了，其中一些基因需要进一步更集中的研究，特别是在 PARP 抑制和 HR 缺陷的情况下。
