High frequency of pathogenic germline variants within homologous recombination repair in patients with advanced cancer
High frequency of pathogenic germline variants within homologous recombination repair in patients with advanced cancer
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DOI：
10.1038/s41525-019-0087-6
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发表时间：
2019-06-21
影响因子：
5.3
通讯作者：
Nielsen, Finn Cilius
中科院分区：
文献类型：
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作者：
Bertelsen, Birgitte;Tuxen, Ida Viller;Nielsen, Finn Cilius
癌症患者的易感变异基因组筛查传统上是基于发病年龄、家族史和癌症类型。尽管临床指南已被证明在识别表现出遗传性癌症的经典属性的家族方面是有效的，但具有替代表现的患者的频率尚不清楚。我们使用全外显子组测序鉴定并表征了636例晚期实体癌患者的生殖系变异。考虑了与遗传性癌症相关的168个基因中的致病性和可能致病的种系变异。这些变异在17.8%的患者中被发现，并且在广泛的癌症类型中被发现。尤其是间皮瘤、卵巢癌、宫颈癌、尿路上皮癌和原发灶不明的癌症患者，其致病性变异频率较高。变异体主要存在于DNA修复途径中，约一半在参与同源重组修复的基因内。在12种不同的癌症类型中发现了22种BRCA1和BRCA2生殖系变异，其中10种（45%）以前未在这些患者中发现。在几个受影响的基因中发现了杂合性丢失和体细胞二次命中，支持癌症发展的可能因果关系。在25例患者（4%）中，可以建议基于致病性生殖系变异的潜在治疗靶点。该研究表明，在晚期实体癌患者中，同源重组途径中致病性种系变异的频率很高。我们推断，在这组患者中进行遗传筛查可能会发现高风险家族，并识别出患有潜在PARP抑制剂敏感性肿瘤的患者。
Genomic screening of cancer patients for predisposing variants is traditionally based on age at onset, family history and type of cancer. Whereas the clinical guidelines have proven efficient in identifying families exhibiting classical attributes of hereditary cancer, the frequency of patients with alternative presentations is unclear. We identified and characterized germline variants in 636 patients with advanced solid cancer using whole exome sequencing. Pathogenic and likely pathogenic germline variants among 168 genes associated with hereditary cancer were considered. These variants were identified in 17.8% of the patients and within a wide range of cancer types. In particular, patients with mesothelioma, ovarian cancer, cervical cancer, urothelial cancer, and cancer of unknown primary origin displayed high frequencies of pathogenic variants. Variants were predominantly found in DNA-repair pathways and about half were within genes involved in homologous recombination repair. Twenty-two BRCA1 and BRCA2 germline variants were identified in 12 different cancer types, of which 10 (45%) were not previously identified in these patients based on the current clinical guidelines. Loss of heterozygosity and somatic second hits were identified in several of the affected genes, supporting possible causality for cancer development. A potential treatment target based on the pathogenic germline variant could be suggested in 25 patients (4%). The study demonstrates a high frequency of pathogenic germline variants in the homologous recombination pathway in patients with advanced solid cancers. We infer that genetic screening in this group of patients may reveal high-risk families and identify patients with potential PARP inhibitor sensitive tumors.