Biomarkers for Homologous Recombination Deficiency in Cancer
Biomarkers for Homologous Recombination Deficiency in Cancer
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DOI：
10.1093/jnci/djy085
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发表时间：
2018-07-01
影响因子：
10.3
通讯作者：
Jeyasekharan, Anand D.
中科院分区：
文献类型：
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作者：
Hoppe, Michal M.;Sundar, Raghav;Jeyasekharan, Anand D.
DNA修复缺陷是癌症的常见特征。由于同源重组缺陷细胞对多adp核糖聚合酶（PARP）抑制剂的敏感性，同源重组是一种具有临床意义的DNA修复途径。因此，测量癌症中的同源重组缺陷（HRD）对于适当设计含有PARP抑制剂的临床试验至关重要。然而，确定肿瘤中HRD的方法多种多样且存在争议。了解现有的和新的HRD测量方法对于在临床试验和实践中适当使用这些方法非常重要。本综述的目的是总结当前测量HRD方法的生物学和临床验证，以帮助PARP抑制剂试验中患者分层和转化研究的决策。我们讨论了PARP抑制剂目前的临床发展，以及HRD的既定指标，如种系BRCA1/2突变状态和对铂基治疗的临床反应。然后，我们研究了正在进行临床验证的新分析，包括1)同源重组基因的体细胞突变，2)使用基于阵列的比较基因组杂交（aCGH）的“基因组疤痕”分析，单核苷酸多态性（SNP）分析或来自下一代测序的突变特征，3)HRD的转录谱，以及4)蛋白质表达和定位的表型或功能分析。我们强调了每种检测方法的优点和缺点，以便在设计涉及PARP抑制剂的研究时加以考虑。
Defective DNA repair is a common hallmark of cancer. Homologous recombination is a DNA repair pathway of clinical interest due to the sensitivity of homologous recombination-deficient cells to poly-ADP ribose polymerase (PARP) inhibitors. The measurement of homologous recombination deficiency (HRD) in cancer is therefore vital to the appropriate design of clinical trials incorporating PARP inhibitors. However, methods to identify HRD in tumors are varied and controversial. Understanding existing and new methods to measure HRD is important to their appropriate use in clinical trials and practice. The aim of this review is to summarize the biology and clinical validation of current methods to measure HRD, to aid decision-making for patient stratification and translational research in PARP inhibitor trials. We discuss the current clinical development of PARP inhibitors, along with established indicators for HRD such as germline BRCA1/2 mutation status and clinical response to platinum-based therapy. We then examine newer assays undergoing clinical validation, including 1) somatic mutations in homologous recombination genes, 2) "genomic scar" assays using array-based comparative genomic hybridization (aCGH), single nucleotide polymorphism(SNP) analysis or mutational signatures derived from next-generation sequencing, 3) transcriptional profiles of HRD, and 4) phenotypic or functional assays of protein expression and localization. We highlight the strengths and weaknesses of each of these assays, for consideration during the design of studies involving PARP inhibitors.