Homologous recombination deficiency (HRD) testing in ovarian cancer clinical practice: a review of the literature.
Homologous recombination deficiency (HRD) testing in ovarian cancer clinical practice: a review of the literature.
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DOI：
10.1186/s40661-017-0039-8
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发表时间：
2017
期刊：
影响因子：
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通讯作者：
Pothuri B
中科院分区：
文献类型：
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作者：
Frey MK;Pothuri B
直到最近，我们对卵巢癌的遗传贡献的了解几乎完全集中在BRCA1/2基因的突变上。然而，通过生殖系和肿瘤测序，人们已经对同源重组缺陷(HRD)这一更大的现象有了理解。HRD损害正常的DNA损伤修复，导致染色体区域的丢失或复制，称为基因组杂合性丢失(LOH)。与卵巢癌相关的遗传突变列表继续增加，目前有文献表明，多达四分之一的病例将具有生殖系突变，其中大部分会导致HRD。此外，另外5%-7%的卵巢癌病例将出现躯体HRD。在不久的将来，除了多聚(ADP-核糖)聚合酶(PARP)抑制剂外，生殖系或体细胞HRD患者可能成为越来越多的靶向治疗的候选对象，因此，建立广泛的HRD测试基础设施势在必行。这篇综述文章的目的是集中于目前卵巢癌的生殖系和躯体致癌因素以及生殖系和躯体HRD检测的状况。目前，生殖系和体细胞肿瘤检测提供了重要且不重叠的临床信息。我们将探索一种拟议的检测策略，将体细胞肿瘤检测作为初始分诊，将体细胞检测发现有HRD基因突变的患者转至遗传学，以确定突变是否为生殖系。这一策略允许快速获取基因组信息，这些信息可以指导有针对性的治疗决定，并减轻遗传顾问的负担，遗传顾问通常是一种有限的资源，他们只会去看体细胞分类测试呈阳性的患者。
Until recently our knowledge of a genetic contribution to ovarian cancer focused almost exclusively on mutations in the BRCA1/2 genes. However, through germline and tumor sequencing an understanding of the larger phenomenon of homologous recombination deficiency (HRD) has emerged. HRD impairs normal DNA damage repair which results in loss or duplication of chromosomal regions, termed genomic loss of heterozygosity (LOH). The list of inherited mutations associated with ovarian cancer continues to grow with the literature currently suggesting that up to one in four cases will have germline mutations, the majority of which result in HRD. Furthermore, an additional 5–7% of ovarian cancer cases will have somatic HRD. In the near future, patients with germline or somatic HRD will likely be candidates for a growing list of targeted therapies in addition to poly (ADP-ribose) polymerase (PARP) inhibitors, and, as a result, establishing an infrastructure for widespread HRD testing is imperative. The objective of this review article is to focus on the current germline and somatic contributors to ovarian cancer and the state of both germline and somatic HRD testing. For now, germline and somatic tumor testing provide important and non-overlapping clinical information. We will explore a proposed testing strategy using somatic tumor testing as an initial triage whereby those patients found with somatic testing to have HRD gene mutations are referred to genetics to determine if the mutation is germline. This strategy allows for rapid access to genomic information that can guide targeted treatment decisions and reduce the burden on genetic counselors, an often limited resource, who will only see patients with a positive somatic triage test.