Genetic polymorphisms predict development of trastuzumab-induced cardiotoxicity

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K08541
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: Kyushu University
• Principal Investigator: Kisho Ohtani 九州大学, 医学研究院, 共同研究員 (60380408)
• Co-Investigator(Kenkyū-buntansha): 久保 真 九州大学, 大学病院, 講師 (60403961) ; 山下 奈真 九州大学, 大学病院, 助教 (60608967) ; 秋吉 清百合 九州大学, 大学病院, 助教 (50567360) ; 筒井 裕之 九州大学, 医学研究院, 教授 (70264017) ; 井手 友美 九州大学, 医学研究院, 准教授 (90380625)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: トラスツズマブ / 心毒性 / ゲノム変異 / 挿入欠失配列 / 一塩基多様性

Outline of Final Research Achievements

This study aimed to identify novel causative genetic mutations and elucidate the association between the mutations and pathogenesis. Based on our previous results, we hypothesized that genetic factors, in addition to environmental factors, played an essential role in the development of trastuzumab-induced cardiotoxicity (TIC). To identify specific genetic variants which make the patients susceptible to TIC, whole-exome sequencing of germline DNA samples from 21 patients developing TIC and 21 who did not experience TIC was performed. Genomic variants were detected, including 234 insertion-deletion (InDel) mutations and 3,085 single nucleotide variants (SNVs) observed in the TIC group and not found in the unaffected group. Among them, a mutation at a locus on chromosome 5 (TRIM7: NM_203297: exon5: c.684_685insTTT: p.F229delinsFF) was statistically significant (p<0.05), suggesting that it may be a candidate mutation causing TIC.

Free Research Field

循環器内科学

Academic Significance and Societal Importance of the Research Achievements

本研究では本邦独自のトラスツズマブ誘発心毒性の臨床像及び実態を明らかにした。厳格な基準を満たしたトラスツズマブ誘発心毒性発症群と未発症群での差異から、新規原因候補遺伝子、新規塩基配列変化を同定することができた。今回の候補変異が病態に及ぼす意義を解明するには、更なる症例の集積およびin vitroアッセイ系での解析が必要である。今後の更なる検討により、心毒性を回避し、より安全なトラスツズマブ治療の提供に結びつくことが期待される。