Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Illinois.
Department of Human Genetics, The University of Chicago, Illinois.
JAMA Netw Open. 2023 Aug 1;6(8):e2327351. doi: 10.1001/jamanetworkopen.2023.27351.
Patients with mesothelioma often have next-generation sequencing (NGS) of their tumor performed; tumor-only NGS may incidentally identify germline pathogenic or likely pathogenic (P/LP) variants despite not being designed for this purpose. It is unknown how frequently patients with mesothelioma have germline P/LP variants incidentally detected via tumor-only NGS.
To determine the prevalence of incidental germline P/LP variants detected via tumor-only NGS of mesothelioma.
DESIGN, SETTING, AND PARTICIPANTS: A series of 161 unrelated patients with mesothelioma from a high-volume mesothelioma program had tumor-only and germline NGS performed during April 2016 to October 2021. Follow-up ranged from 18 months to 7 years. Tumor and germline assays were compared to determine which P/LP variants identified via tumor-only NGS were of germline origin. Data were analyzed from January to March 2023.
The proportion of patients with mesothelioma who had P/LP germline variants incidentally detected via tumor-only NGS.
Of 161 patients with mesothelioma, 105 were male (65%), the mean (SD) age was 64.7 (11.2) years, and 156 patients (97%) self-identified as non-Hispanic White. Most (126 patients [78%]) had at least 1 potentially incidental P/LP germline variant. The positive predictive value of a potentially incidental germline P/LP variant on tumor-only NGS was 20%. Overall, 26 patients (16%) carried a P/LP germline variant. Germline P/LP variants were identified in ATM, ATR, BAP1, CHEK2, DDX41, FANCM, HAX1, MRE11A, MSH6, MUTYH, NF1, SAMD9L, and TMEM127.
In this case series of 161 patients with mesothelioma, 16% had confirmed germline P/LP variants. Given the implications of a hereditary cancer syndrome diagnosis for preventive care and familial counseling, clinical approaches for addressing incidental P/LP germline variants in tumor-only NGS are needed. Tumor-only sequencing should not replace dedicated germline testing. Universal germline testing is likely needed for patients with mesothelioma.
间皮瘤患者通常会对其肿瘤进行下一代测序（NGS）；尽管并非为此目的设计，但肿瘤仅 NGS 可能会偶然识别出种系致病性或可能致病性（P/LP）变体。目前尚不清楚间皮瘤患者通过肿瘤仅 NGS 偶然检测到种系 P/LP 变体的频率。
确定通过间皮瘤肿瘤仅 NGS 偶然检测到的种系 P/LP 变体的患病率。
设计、设置和参与者：2016 年 4 月至 2021 年 10 月期间，对来自高容量间皮瘤计划的 161 名无关间皮瘤患者进行了肿瘤和种系 NGS。随访时间从 18 个月到 7 年不等。比较肿瘤和种系检测结果，以确定通过肿瘤仅 NGS 鉴定的哪些 P/LP 变体源自种系。数据分析于 2023 年 1 月至 3 月进行。
通过肿瘤仅 NGS 偶然检测到间皮瘤患者的种系 P/LP 变体的比例。
在 161 名间皮瘤患者中，105 名男性（65%），平均（SD）年龄为 64.7（11.2）岁，156 名患者（97%）自我认定为非西班牙裔白人。大多数（126 名患者[78%]）至少有 1 种潜在的偶然 P/LP 种系变体。肿瘤仅 NGS 上潜在偶然种系 P/LP 变体的阳性预测值为 20%。总体而言，26 名患者（16%）携带 P/LP 种系变体。在 ATM、ATR、BAP1、CHEK2、DDX41、FANCM、HAX1、MRE11A、MSH6、MUTYH、NF1、SAMD9L 和 TMEM127 中发现了种系 P/LP 变体。
在这项 161 名间皮瘤患者的病例系列研究中，16%的患者被确诊为种系 P/LP 变体。鉴于遗传性癌症综合征诊断对预防保健和家族咨询的影响，需要针对肿瘤仅 NGS 中偶然的 P/LP 种系变体制定临床方法。肿瘤仅测序不应替代专门的种系检测。间皮瘤患者可能需要进行普遍的种系检测。
