Whole exome sequencing to identify genetic markers for trastuzumab-induced cardiotoxicity.

Abstract

Although trastuzumab-induced cardiotoxicity is an important determinant to limit the use of this drug, the molecular mechanism of risk for this toxicity is not well understood. To identify genetic variants determining the risk of trastuzumab-induced cardiotoxicity, we carried out whole exome sequencing of germline DNA samples from 9 patients with trastuzumab-induced cardiotoxicity, and conducted a case-control association study of 2258 genetic variants between 9 cases (with trastuzumab-induced cardiotoxicity) and general Japanese population controls registered in the Human Genetic Variation Database (HGVD). The top variant which showed the lowest P-value in the screening study was rs139503277 in PHD Finger Protein 3 (Pmin = .00012, odds ratio [OR] = 51.23). To further validate the result of screening study, we carried out a replication study of 10 variants showing Pmin < .001 in the screening study using 234 independent patients treated with trastuzumab, including 10 cases and 224 controls (without trastuzumab-induced cardiotoxicity). In the replication study, we observed that three variants had an effect in the same direction as in the screening study (rs78272919 in exon 2 of Keratin 15, rs5762940 in exon 2 of zinc and ring finger 3, and rs139944387 in exon 44 of Eyes shut homologs [EYS]). A combined result of the screening and the replication studies suggested an association of a locus on chromosome 6q12 with trastuzumab-induced cardiotoxicity (rs139944387 in EYS, combined Pmin = .00056, OR = 13.73). This finding provides new insights into personalized trastuzumab therapy for patients with human epidermal growth factor receptor 2 (HER2)-positive cancer.

• Authors: Chihiro Udagawa, Hiromi Nakamura, Hiroshi Ohnishi, Kenji Tamura, Tatsunori Shimoi, Masayuki Yoshida, Teruhiko Yoshida, Yasushi Totoki, Tatsuhiro Shibata, Hitoshi Zembutsu
• Journal: Cancer science (Cancer Sci) Vol. 109 Issue 2 Pg. 446-452 (Feb 2018) ISSN: 1349-7006 [Electronic] England
• PMID: 29247589 (Publication Type: Journal Article)
• Copyright: © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Chemical References

• EYS protein, human
• Eye Proteins
• Genetic Markers
• KRT15 protein, human
• Keratin-15
• PHF3 protein, human
• Transcription Factors
• Ubiquitin-Protein Ligases
• ZNRF3 protein, human
• Trastuzumab

Topics

• Adult
• Aged
• Aged, 80 and over
• Cardiotoxicity (genetics)
• Case-Control Studies
• Eye Proteins (genetics)
• Female
• Genetic Markers (genetics)
• Germ-Line Mutation
• Humans
• Keratin-15 (genetics)
• Male
• Middle Aged
• Polymorphism, Single Nucleotide
• Transcription Factors (genetics)
• Trastuzumab (toxicity)
• Ubiquitin-Protein Ligases (genetics)
• Exome Sequencing (methods)