Tung Nadine, Dougherty Kali Chatham, Gatof Emily Stern, DeLeonardis Kim, Hogan Lauren, Tukachinsky Hanna, Gornstein Erica, Oxnard Geoffrey R, McGregor Kimberly, Keller Rachel B
Department of Medical Oncology, Beth Israel Deaconess Medical Center, Boston, MA, USA.
Foundation Medicine, Inc., Cambridge, MA, USA.
NPJ Precis Oncol. 2023 Aug 11;7(1):76. doi: 10.1038/s41698-023-00429-1.
Existing guidance regarding clinically informed germline testing for patients with cancer is effective for evaluation of classic hereditary cancer syndromes and established gene/cancer type associations. However, current screening methods may miss patients with rare, reduced penetrance, or otherwise occult hereditary risk. Secondary finding of suspected germline variants that may confer inherited cancer risk via tumor comprehensive genomic profiling (CGP) has the potential to help address these limitations. However, reporting practices for secondary finding of germline variants are inconsistent, necessitating solutions for transparent and coherent communication of these potentially important findings. A workflow for improved confidence detection and clear reporting of potential pathogenic germline variants (PPGV) in select cancer susceptibility genes (CSG) was applied to a research dataset from real-world clinical tumor CGP of > 125,000 patients with advanced cancer. The presence and patterns of PPGVs identified across tumor types was assessed with a focus on scenarios in which traditional clinical germline evaluation may have been insufficient to capture genetic risk. PPGVs were identified in 9.7% of tumor CGP cases using tissue- and liquid-based assays across a broad range of cancer types, including in a number of "off-tumor" contexts. Overall, PPGVs were identified in a similar proportion of cancers with National Comprehensive Cancer Network (NCCN) recommendations for germline testing regardless of family history (11%) as in all other cancer types (9%). These findings suggest that tumor CGP can serve as a tool that is complementary to traditional germline genetic evaluation in helping to ascertain inherited susceptibility in patients with advanced cancer.
现有的关于为癌症患者进行临床知情种系检测的指南，对于评估经典遗传性癌症综合征以及已确立的基因/癌症类型关联是有效的。然而，当前的筛查方法可能会遗漏那些具有罕见、低外显率或其他隐匿遗传风险的患者。通过肿瘤综合基因组分析（CGP）发现可能通过种系变异导致遗传性癌症风险的次要结果，有可能帮助解决这些局限性。然而，种系变异次要结果的报告做法并不一致，因此需要有解决方案来透明且连贯地传达这些潜在的重要发现。一种用于提高对选定癌症易感基因（CSG）中潜在致病性种系变异（PPGV）的检测可信度并进行清晰报告的工作流程，被应用于来自超过125,000例晚期癌症患者的真实世界临床肿瘤CGP研究数据集。评估了在各种肿瘤类型中识别出的PPGV的存在情况和模式，重点关注传统临床种系评估可能不足以捕捉遗传风险的情况。使用基于组织和液体的检测方法，在广泛的癌症类型中，包括在一些“非肿瘤”情况下，9.7%的肿瘤CGP病例中识别出了PPGV。总体而言，无论家族史如何，在符合美国国立综合癌症网络（NCCN）种系检测建议的癌症中，识别出PPGV的比例（11%）与所有其他癌症类型（9%）相似。这些发现表明，肿瘤CGP可作为一种工具，在帮助确定晚期癌症患者的遗传易感性方面，是对传统种系基因评估的补充。
