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.

传统上，基于发病年龄，家族病史和癌症类型对癌症患者进行基因组筛选以寻找易感的变异体。尽管临床指南已被证明可以有效地识别出具有遗传性癌症经典特征的家庭，但尚不清楚有其他表现形式的患者的频率。我们使用全外显子组测序在636例晚期实体癌患者中鉴定并鉴定了种系变异。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。这些变体在17.8％的患者中和多种癌症类型中均得到鉴定。特别是，间皮瘤，卵巢癌，宫颈癌，尿路上皮癌和原发性未知的癌症患者表现出高频率的致病变异。主要在DNA修复途径中发现变体，大约一半在与同源重组修复有关的基因中。二十二在当前的临床指南中，在12种不同的癌症类型中鉴定出BRCA1和BRCA2种系变异体，其中先前未在这些患者中鉴定出10种（45％）。在几个受影响的基因中鉴定出杂合性和体细胞第二击的丧失，支持了癌症发展的可能因果关系。可以建议在25例患者中（4％）基于病原种系的潜在治疗目标。这项研究表明，在晚期实体癌患者中，同源重组途径中的致病性种系变异频率很高。我们推断，在这组患者中进行基因筛查可能会揭示高危家庭，并确定患有潜在的PARP抑制剂敏感肿瘤的患者。