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Whole exome sequencing to identify genetic markers for trastuzumab‐induced cardiotoxicity
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 sequenc...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5797809/ https://www.ncbi.nlm.nih.gov/pubmed/29247589 http://dx.doi.org/10.1111/cas.13471 |
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author | Udagawa, Chihiro Nakamura, Hiromi Ohnishi, Hiroshi Tamura, Kenji Shimoi, Tatsunori Yoshida, Masayuki Yoshida, Teruhiko Totoki, Yasushi Shibata, Tatsuhiro Zembutsu, Hitoshi |
author_facet | Udagawa, Chihiro Nakamura, Hiromi Ohnishi, Hiroshi Tamura, Kenji Shimoi, Tatsunori Yoshida, Masayuki Yoshida, Teruhiko Totoki, Yasushi Shibata, Tatsuhiro Zembutsu, Hitoshi |
author_sort | Udagawa, Chihiro |
collection | PubMed |
description | 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 (P (min) = .00012, odds ratio [OR] = 51.23). To further validate the result of screening study, we carried out a replication study of 10 variants showing P (min) < .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 P (min) = .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. |
format | Online Article Text |
id | pubmed-5797809 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-57978092018-02-14 Whole exome sequencing to identify genetic markers for trastuzumab‐induced cardiotoxicity Udagawa, Chihiro Nakamura, Hiromi Ohnishi, Hiroshi Tamura, Kenji Shimoi, Tatsunori Yoshida, Masayuki Yoshida, Teruhiko Totoki, Yasushi Shibata, Tatsuhiro Zembutsu, Hitoshi Cancer Sci Original Articles 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 (P (min) = .00012, odds ratio [OR] = 51.23). To further validate the result of screening study, we carried out a replication study of 10 variants showing P (min) < .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 P (min) = .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. John Wiley and Sons Inc. 2018-01-24 2018-02 /pmc/articles/PMC5797809/ /pubmed/29247589 http://dx.doi.org/10.1111/cas.13471 Text en © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial (http://creativecommons.org/licenses/by-nc/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. |
spellingShingle | Original Articles Udagawa, Chihiro Nakamura, Hiromi Ohnishi, Hiroshi Tamura, Kenji Shimoi, Tatsunori Yoshida, Masayuki Yoshida, Teruhiko Totoki, Yasushi Shibata, Tatsuhiro Zembutsu, Hitoshi Whole exome sequencing to identify genetic markers for trastuzumab‐induced cardiotoxicity |
title | Whole exome sequencing to identify genetic markers for trastuzumab‐induced cardiotoxicity |
title_full | Whole exome sequencing to identify genetic markers for trastuzumab‐induced cardiotoxicity |
title_fullStr | Whole exome sequencing to identify genetic markers for trastuzumab‐induced cardiotoxicity |
title_full_unstemmed | Whole exome sequencing to identify genetic markers for trastuzumab‐induced cardiotoxicity |
title_short | Whole exome sequencing to identify genetic markers for trastuzumab‐induced cardiotoxicity |
title_sort | whole exome sequencing to identify genetic markers for trastuzumab‐induced cardiotoxicity |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5797809/ https://www.ncbi.nlm.nih.gov/pubmed/29247589 http://dx.doi.org/10.1111/cas.13471 |
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