Schneider Bryan P, Stout Leigh Anne, Philips Santosh, Schroeder Courtney, Scott Susanna F, Hunter Cynthia, Kassem Nawal, Kiel Patrick J, Radovich Milan
Indiana University School of Medicine, Indianapolis, IN.
Indiana University Health Precision Genomics, Indianapolis, IN.
JCO Precis Oncol. 2020 Nov;4:1109-1121. doi: 10.1200/PO.19.00354.
Identification of incidental germline mutations in the context of next-generation sequencing is an unintended consequence of advancing technologies. These data are critical for family members to understand disease risks and take action.
A retrospective cohort analysis was conducted of 1,028 adult patients with metastatic cancer who were sequenced with tumor and germline whole exome sequencing (WES). Germline variant call files were mined for pathogenic/likely pathogenic (P/LP) variants using the ClinVar database and narrowed to high-quality submitters.
Median age was 59 years, with 16% of patients ≤ 45 years old. The most common tumor types were breast cancer (12.5%), colorectal cancer (11.5%), sarcoma (9.3%), prostate cancer (8.4%), and lung cancer (6.6%). We identified 3,427 P/LP variants in 471 genes, and 84% of patients harbored one or more variant. One hundred thirty-two patients (12.8%) carried a P/LP variant in a cancer predisposition gene, with being the most common (1.6%). Patients with breast cancer were most likely to carry a P/LP variant (19.2%). One hundred ten patients (10.7%) carried a P/LP variant in a gene that would be recommended by the American College of Medical Genetics and Genomics to be reported as a result of clinical actionability, with the most common being (2.7%), (1.6%), (1.4%), and (1%). Of patients who carried a P/LP variant in a cancer predisposition gene, only 53% would have been offered correct testing based on current clinical practice guidelines. Of 471 mutated genes, 231 genes had a P/LP variant identified in one patient, demonstrating significant genetic heterogeneity.
The majority of patients undergoing clinical cancer WES harbor a pathogenic germline variation. Identification of clinically actionable germline findings will create additional burden on oncology clinics as broader WES becomes common.
在下一代测序背景下识别偶然的种系突变是技术进步带来的意外结果。这些数据对于家庭成员了解疾病风险并采取行动至关重要。
对1028例成年转移性癌症患者进行了回顾性队列分析，这些患者接受了肿瘤和种系全外显子测序（WES）。使用ClinVar数据库挖掘种系变异调用文件中的致病/可能致病（P/LP）变异，并将范围缩小至高质量提交者。
中位年龄为59岁，16%的患者年龄≤45岁。最常见的肿瘤类型为乳腺癌（12.5%）、结直肠癌（11.5%）、肉瘤（9.3%）、前列腺癌（8.4%）和肺癌（6.6%）。我们在471个基因中鉴定出3427个P/LP变异，84%的患者携带一个或多个变异。132例患者（12.8%）在癌症易感基因中携带P/LP变异，其中 最为常见（1.6%）。乳腺癌患者携带P/LP变异的可能性最高（19.2%）。110例患者（10.7%）在因临床可操作性而被美国医学遗传学与基因组学学会推荐报告的基因中携带P/LP变异，其中最常见的是 （2.7%）、 （1.6%）、 （1.4%）和 （1%）。在癌症易感基因中携带P/LP变异的患者中，根据当前临床实践指南，只有53%的患者会接受正确的检测。在471个突变基因中，231个基因在一名患者中鉴定出P/LP变异，显示出显著的遗传异质性。
大多数接受临床癌症WES的患者携带致病种系变异。随着更广泛的WES变得普遍，识别具有临床可操作性的种系发现将给肿瘤诊所带来额外负担。
