Division of Genetic Counseling, Genetic Medicine Promotion, Shizuoka Cancer Center Hospital, Shizuoka, Japan.
Department of Psychiatry and Behavioral Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
Hum Genet. 2021 Feb;140(2):321-331. doi: 10.1007/s00439-020-02207-6. Epub 2020 Jul 24.
High-throughput sequencing has greatly contributed to precision medicine. However, challenges remain in reporting secondary findings (SFs) of germline pathogenic variants and managing the affected patients. The aim of this study was to examine the incidence of SFs in Japanese cancer patients using whole exome sequencing (WES) and to understand patient preferences regarding SF disclosure. WES was conducted for 2480 cancer patients. Genomic data were screened and classified for variants of 59 genes listed by the American College of Medical Genetics and Genomics SF v2.0 and for an additional 13 hereditary cancer-related genes. Majority of the participants (68.9%; 1709/2480) opted for disclosure of their SFs. Thirty-two pathogenic or likely pathogenic variants, including BRCA1 (7 patients), BRCA2 (4), CHEK2 (4), PTEN (3), MLH1 (3), SDHB (2), MSH6 (1), NF1 (1), EXT2 (1), NF1 (1), NTRK1 (1), MYH7 (3), MYL2 (1), TNNT2 (1), LDLR (2), FBN1 (1), and KCNH2 (1) were recognized in 36 patients (1.5%). Twenty-eight (77.8%) patients underwent genetic counseling and received their SF results. Eighteen (64.3%) patients underwent clinical management for SFs. Genetic validation tests were administered significantly more frequently to patients with than without a SF-related personal history (P = 0.025). This was a first attempt at a large-scale systematic exome analysis in Japan; nevertheless, many cancer patients opted for disclosure of SFs and accepted or considered clinical management.
高通量测序极大地推动了精准医学的发展。然而，在报告种系致病性变异的次要发现 (SFs) 和管理受影响的患者方面仍然存在挑战。本研究旨在通过全外显子组测序 (WES) 检查日本癌症患者 SFs 的发生率，并了解患者对 SF 披露的偏好。对 2480 名癌症患者进行了 WES。对 59 个基因列表中的变异进行了基因组数据筛选和分类，这些基因是由美国医学遗传学和基因组学学院 SF v2.0 列出的，以及另外 13 个遗传性癌症相关基因。大多数参与者 (68.9%；1709/2480) 选择披露他们的 SFs。32 个致病性或可能致病性的变异，包括 BRCA1(7 例)、BRCA2(4 例)、CHEK2(4 例)、PTEN(3 例)、MLH1(3 例)、SDHB(2 例)、MSH6(1 例)、NF1(1 例)、EXT2(1 例)、NF1(1 例)、NTRK1(1 例)、MYH7(3 例)、MYL2(1 例)、TNNT2(1 例)、LDLR(2 例)、FBN1(1 例)和 KCNH2(1 例)，在 36 名患者(1.5%)中得到了确认。28 名(77.8%)患者接受了遗传咨询并获得了他们的 SF 结果。18 名(64.3%)患者对 SFs 进行了临床管理。对有 SF 相关个人病史的患者进行基因验证测试的频率显著高于无 SF 相关个人病史的患者 (P=0.025)。这是日本首次对大规模系统外显子组进行分析；然而，许多癌症患者选择披露 SFs，并接受或考虑进行临床管理。
