High-risk pathogenic germline variants in blood relatives of BRCA1/2 negative probands.

IF 4 3区医学 Q1 OBSTETRICS & GYNECOLOGY Breast Cancer Pub Date : 2024-11-01 Epub Date: 2024-07-13 DOI:10.1007/s12282-024-01615-0

Reiko Yoshida, Tomoko Kaneyasu, Arisa Ueki, Hideko Yamauchi, Shozo Ohsumi, Shinji Ohno, Daisuke Aoki, Shinichi Baba, Junko Kawano, Naomichi Matsumoto, Masao Nagasaki, Takayuki Ueno, Hitoshi Inari, Yusuke Kobayashi, Junko Takei, Osamu Gotoh, Mitsuyo Nishi, Miki Okamura, Keika Kaneko, Megumi Okawa, Misato Suzuki, Sayuri Amino, Mayuko Inuzuka, Tetsuo Noda, Seiichi Mori, Seigo Nakamura

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Abstract

Background: 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.

Methods: PGV prevalence was assessed for 682 BRs of 281 probands with BRCA1/BRCA2 wild-type hereditary breast and ovarian cancer (HBOC) syndrome.

Results: 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.

Conclusion: These findings imply the necessity to construct a novel testing scheme to complement cascade testing.

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BRCA1/2 阴性探查者血亲中的高风险致病基因变异。

背景：量身定制的预防性癌症治疗需要在潜在高危血亲（BRs）中识别致病性种系变异（PGVs）。对于遗传性癌症 PGV 呈阳性的原告的血亲，可进行基因串联检测，而对于阴性原告的血亲，则不进行基因串联检测。本研究的目的是检测 PGV 阴性概率者的血亲中 PGV 的流行率：方法：对281名BRCA1/BRCA2野生型遗传性乳腺癌和卵巢癌（HBOC）综合征（hereditary breast and ovarian cancer，HBOC）患者的682个BR进行了PGV流行率评估：结果：在PGV阳性探查者的48个BR中发现了22个（45.8%）PGV，在PGV阴性探查者的634个BR中发现了14个（2.2%）PGV。高风险 BRCA1、BRCA2 和 TP53 基因上的 11 个 PGV 只出现在 BR 中，而不出现在探针中（费舍尔精确检验中探针与 BR 的比值；P = 0.0104；比值比 [OR] = 0.000 [0.000-0.5489 的 95% 置信区间]），部分原因是选择标准的性质。与非癌症东亚人群相比，BRs 中高风险 PGV 的富集也很显著（p = 0.0016；OR = 3.0791 [1.5521-5.6694]）。PGV的流行率、基因的风险等级和基因型的一致性在BR人群中不受癌症病史的影响：这些研究结果表明，有必要建立一种新的检测方案来补充级联检测。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Breast Cancer ONCOLOGY-OBSTETRICS & GYNECOLOGY

CiteScore

6.70

自引率

2.50%

发文量

105

审稿时长

6-12 weeks

期刊介绍： Breast Cancer, the official journal of the Japanese Breast Cancer Society, publishes articles that contribute to progress in the field, in basic or translational research and also in clinical research, seeking to develop a new focus and new perspectives for all who are concerned with breast cancer. The journal welcomes all original articles describing clinical and epidemiological studies and laboratory investigations regarding breast cancer and related diseases. The journal will consider five types of articles: editorials, review articles, original articles, case reports, and rapid communications. Although editorials and review articles will principally be solicited by the editors, they can also be submitted for peer review, as in the case of original articles. The journal provides the best of up-to-date information on breast cancer, presenting readers with high-impact, original work focusing on pivotal issues.