Bertelsen Birgitte, Tuxen Ida Viller, Yde Christina Westmose, Gabrielaite Migle, Torp Mathias Husted, Kinalis Savvas, Oestrup Olga, Rohrberg Kristoffer, Spangaard Iben, Santoni-Rugiu Eric, Wadt Karin, Mau-Sorensen Morten, Lassen Ulrik, Nielsen Finn Cilius
1Center for Genomic Medicine, Rigshospitalet, Copenhagen, Denmark.
2The Phase I Unit, Department of Oncology, Rigshospitalet, Copenhagen, Denmark.
NPJ Genom Med. 2019 Jun 21;4:13. doi: 10.1038/s41525-019-0087-6. eCollection 2019.
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 and 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，对癌症患者进行基因组筛查以寻找易感变异是基于发病年龄、家族史和癌症类型。虽然临床指南已被证明在识别具有遗传性癌症典型特征的家族方面是有效的，但具有非典型表现的患者的比例尚不清楚。我们使用全外显子测序对636例晚期实体癌患者的种系变异进行了鉴定和特征分析。我们考虑了与遗传性癌症相关的168个基因中的致病和可能致病的种系变异。在17.8%的患者中发现了这些变异，且涉及多种癌症类型。特别是，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中，致病变异的频率较高。变异主要存在于DNA修复途径中，约一半存在于参与同源重组修复的基因中。在12种不同的癌症类型中鉴定出了22个种系变异，其中10个（45%）根据目前的临床指南在这些患者中未曾被发现。在几个受影响的基因中发现了杂合性缺失和体细胞二次打击，支持了其在癌症发生中的可能因果关系。在25例患者（4%）中可以提出基于致病种系变异的潜在治疗靶点。该研究表明，晚期实体癌患者中同源重组途径的致病种系变异频率较高。我们推断，对这组患者进行基因筛查可能会揭示高危家族，并识别出对PARP抑制剂敏感的潜在肿瘤患者。
