- 著者
- Mari Hara Nakano Chihiro Udagawa Arata Shimo Yasuyuki Kojima Reiko Yoshie Hisamitsu Zaha Norie Abe Tokiwa Motonari Mikiko Unesoko Kenji Tamura Tatsunori Shimoi Masayuki Yoshida Teruhiko Yoshida Hiromi Sakamoto Ken Kato Taisei Mushiroda Koichiro Tsugawa Hitoshi Zembutsu
- 出版者
- The Pharmaceutical Society of Japan
- 雑誌
- Biological and Pharmaceutical Bulletin (ISSN:09186158)
- 巻号頁・発行日
- pp.b19-00527, (Released:2019-10-09)
- 参考文献数
- 42
- 被引用文献数
- 13
Trastuzumab has been administered to patients with HER2-positive cancer, however, the cardiotoxicity is identified as one of the life-threatening toxicities. Clinically useful biomarker for trastuzumab-induced cardiotoxicity has been expected to be developed. To identify a novel genetic marker(s) determining the risk of trastuzumab-induced cardiotoxicity, we performed a first genome-wide association study (GWAS) in Japanese population. We enrolled 481 patients who had been treated with trastuzumab and carried out a GWAS using 11 cases (with cardiotoxicity) and 257 controls (without cardiotoxicity). Top 100 single nucleotide polymorphisms (SNPs) which revealed the smallest P values in GWAS (P = 7.60 x 10-7 - 2.01 x 10-4) were further examined using replication samples consisted of 14 cases and 199 controls. The combined analysis of the GWAS and replication study indicated possible association of five loci with trastuzumab-induced cardiotoxicity (rs9316695 on chromosome 13q14.3, rs28415722 on chromosome 15q26.3, rs7406710 on chromosome 17q25.3, rs11932853 on chromosome 4q25, and rs8032978 on chromosome 15q26.3, Pcombined = 6.00 x 10-6, 8.88 x 10-5, 1.07 x 10-4, 1.42 x 10-4, 1.60 x 10-4, respectively). Furthermore, we developed a risk prediction model for trastuzumab-induced cardiotoxicity using the five marker SNPs. The incidence of trastuzumab-induced cardiotoxicity in patients with risk score ≥ 5 was significantly higher (42.5%) compared to that in patients with score ≤ 4 (1.8%) (P = 7.82 x 10-15, odds ratio = 40.0). These findings suggest the potential to improve the ability of physicians to avoid the trastuzumab-induced cardiotoxicity for patients with HER2-positive cancer.
- 著者
- Kazuhiko OCHIAI Toshina ISHIGURO-OONUMA Yasunaga YOSHIKAWA Chihiro UDAGAWA Yuiko KATO Masami WATANABE Makoto BONKOBARA Masami MORIMATSU Toshinori OMI
- 出版者
- バイオメディカルリサーチプレス
- 雑誌
- Biomedical Research (ISSN:03886107)
- 巻号頁・発行日
- vol.36, no.2, pp.155-158, 2015-04-01 (Released:2015-04-16)
- 参考文献数
- 21
- 被引用文献数
- 2 13
Mutations in the breast cancer susceptibility gene BRCA2 leading to the failure of interactions with the recombinase RAD51 are associated with an increased risk of cancer in humans. This interaction depends on the eight BRC repeat (BRC1–8) sequences in BRCA2. We previously reported that canine BRC3 has two polymorphisms (T1425P and K1435R) influencing the interaction with RAD51, and 1435R was identified in mammary tumor dog samples. In this study, we investigated the sequence variations of BRC3 and 4 in 236 dogs of five breeds. Allele frequencies of 1425P and 1435R were 0.063 and 0.314, respectively, and there was no other polymorphism in the sequenced region. A mammalian two-hybrid assay using BRC3–4 sequences demonstrated that 1425P allele reduced the binding strength with RAD51 but 1435R had no effect. These results may provide an insight into the functions of not only individual but also multiple BRC repeats of BRCA2 in dogs.