肿瘤全基因组分析中潜在的致病性胚系变异报告是对胚系检测试验经典方法的一种补充。
Potential pathogenic germline variant reporting from tumor comprehensive genomic profiling complements classic approaches to germline testing.
发表日期：2023 Aug 11
作者：
Nadine Tung, Kali Chatham Dougherty, Emily Stern Gatof, Kim DeLeonardis, Lauren Hogan, Hanna Tukachinsky, Erica Gornstein, Geoffrey R Oxnard, Kimberly McGregor, Rachel B Keller
来源：
npj Precision Oncology
摘要：
目前关于临床相关的肿瘤患者遗传性基因检测的指导意见，对于评估典型遗传性癌症综合症和已建立的基因/癌症类型关联是有效的。然而，目前的筛查方法可能会错过罕见的、渗透率降低的或其他隐藏的遗传风险的患者。通过肿瘤全面基因组分析（CGP）发现可疑的可能传递遗传性癌症风险的生殖细胞变异物（SGV），有助于解决这些局限性。然而，关于诊断性发现生殖细胞变异物的报告方法不一致，需要透明和首尾一贯的沟通这些潜在重要的发现的解决方案。一个改进的根据特定癌症易感基因的潜在致病性生殖细胞变异物（PPGV）的可信度检测和清晰报告的工作流程被应用于一组来自于真实临床肿瘤全面基因组分析的研究数据集中，包括了超过125,000名晚期癌症患者。评估了在不同肿瘤类型中检测到的PPGV的存在和模式，重点关注传统临床着世细胞评估可能无法捕捉到遗传风险的情形。通过基于组织和液体的分析方法，在广泛的癌症类型中发现了9.7%的肿瘤CGP病例中的PPGV，包括在多种“非肿瘤”环境中。总体而言，PPGV在符合国家综合癌症网络（NCCN）遗传检测推荐的家族病史（11%）和其他所有癌症类型（9%）中都有类似的比例。这些发现表明，肿瘤CGP可以作为一种工具，有助于在晚期癌症患者中辅助传统的遗传性基因评估，以确定遗传易感性。© 2023. Nature Publishing Group UK.
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.© 2023. Nature Publishing Group UK.