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

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2024年7月13日

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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

摘要

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.