BRCA1/2 阴性先证者血亲中的高风险致病性种系变异。
High-risk pathogenic germline variants in blood relatives of BRCA1/2 negative probands.
发表日期：2024 Jul 13
作者：
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
来源：
GENES & DEVELOPMENT
摘要：
量身定制的预防性癌症护理需要识别潜在高危血亲 (BR) 中的致病性种系变异 (PGV)。对遗传性癌症 PGV 呈阳性的先证者的 BR 进行级联测试，但对阴性先证者不进行级联测试。本研究旨在检查 PGV 阴性先证者 BR 的 PGV 患病率。对 281 名患有 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 BR 的 PGV 患病率进行了评估。在 22 名先证者中发现了 PGV。 (45.8%) PGV 阳性先证者的 48 个 BR 和 634 个 PGV 阴性先证者 BR 中的 14 个 (2.2%)。高风险 BRCA1、BRCA2 和 TP53 基因上的 11 个 PGV 仅存在于 BR 中，而不存在于先证者中（Fisher 精确检验中先证者与 BR 的比较；p = 0.0104；优势比 [OR] = 0.000 [0.000-0.5489 of 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，BR 中高风险 PGV 的富集也显着 (p = 0.0016；OR = 3.0791 [1.5521-5.6694])。 PGV 患病率、基因风险类别和基因型一致性不受 BR 中癌症病史的影响。这些发现意味着有必要构建一种新的测试方案来补充级联测试。© 2024。作者。
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.© 2024. The Author(s).