Division of Cancer Genomics, Cancer Institute, Japanese Foundation for Cancer Research (JFCR), 3-8-31 Ariake, Koto-ku, Tokyo, Japan.
Institute for Clinical Genetics and Genomics, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Japan.
Breast Cancer. 2024 Nov;31(6):1028-1036. doi: 10.1007/s12282-024-01615-0. Epub 2024 Jul 13.
Tailored, preventive cancer care requires the identification of pathogenic germline variants (PGVs) among potentially at-risk blood relatives (BRs). Cascade testing is carried out for BRs of probands who are positive for PGVs of an inherited cancer but not for negative probands. This study was conducted to examine the prevalence of PGVs for BRs of PGV-negative probands.
PGV prevalence was assessed for 682 BRs of 281 probands with BRCA1/BRCA2 wild-type hereditary breast and ovarian cancer (HBOC) syndrome.
PGVs were discovered in 22 (45.8%) of the 48 BRs of the PGV-positive probands and in 14 (2.2%) of 634 BRs of the PGV-negative probands. Eleven PGVs on high-risk BRCA1, BRCA2, and TP53 genes were present only in BRs and not in the probands (probands vs BRs in Fisher exact test; p = 0.0104; odds ratio [OR] = 0.000 [0.000-0.5489 of 95% confidence interval]), partly due to the nature of the selection criteria. The enrichment of high-risk PGVs among BRs was also significant as compared with a non-cancer East Asian population (p = 0.0016; OR = 3.0791 [1.5521-5.6694]). PGV prevalence, risk class of gene, and genotype concordance were unaffected by the cancer history among BRs.
These findings imply the necessity to construct a novel testing scheme to complement cascade testing.
定制化的预防性癌症护理需要在有潜在风险的血缘亲属（BRs）中识别致病性种系变异（PGVs）。对种系检测呈阳性的先证者的 BRs 进行级联检测，但对种系检测呈阴性的先证者不进行。本研究旨在检测种系检测呈阴性的先证者的 BRs 中 PGV 的发生率。
对 281 名种系检测呈 BRCA1/BRCA2 野生型遗传性乳腺癌和卵巢癌（HBOC）综合征的先证者的 682 名 BRs 进行 PGV 发生率评估。
在 22 名（45.8%）种系检测呈阳性的先证者的 48 名 BRs 中发现了 PGVs，在 634 名种系检测呈阴性的先证者的 14 名 BRs 中发现了 14 名（种系检测呈阳性的先证者与种系检测呈阴性的先证者的 BRs 相比，Fisher 确切检验；p=0.0104；比值比[OR]=0.000[0.000-0.5489]，95%置信区间）存在仅在 BRs 中而不在先证者中发现的 11 个高危 BRCA1、BRCA2 和 TP53 基因 PGVs，部分原因是选择标准的性质。与非癌症东亚人群相比，BRs 中高危 PGVs 的富集也具有显著意义（p=0.0016；OR=3.0791[1.5521-5.6694]）。BRs 中的癌症病史对 PGV 发生率、基因风险类别和基因型一致性没有影响。
这些发现意味着有必要构建一种新的检测方案来补充级联检测。
