학술논문
Genetic association of gemcitabine/carboplatin-induced leukopenia and neutropenia in non-small cell lung cancer patients using whole-exome sequencing.
Document Type
Academic Journal
Author
Svedberg A; Clinical Pharmacology, Division of Drug Research, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.; Björn N; Clinical Pharmacology, Division of Drug Research, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.; Sigurgeirsson B; Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, Department of Gene Technology, KTH Royal Institute of Technology, Solna, Sweden; School of Engineering and Natural Sciences, University of Iceland, Reykjavík, Iceland.; Pradhananga S; Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, Department of Gene Technology, KTH Royal Institute of Technology, Solna, Sweden.; Brandén E; Department of Respiratory Medicine, Gävle Hospital, Gävle, Sweden; Centre for Research and Development, Uppsala University/Region Gävleborg, Gävle, Sweden.; Koyi H; Department of Respiratory Medicine, Gävle Hospital, Gävle, Sweden; Centre for Research and Development, Uppsala University/Region Gävleborg, Gävle, Sweden.; Lewensohn R; Thoracic Oncology Unit, Tema Cancer, Karolinska University Hospital, and Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.; De Petris L; Thoracic Oncology Unit, Tema Cancer, Karolinska University Hospital, and Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.; Apellániz-Ruiz M; Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.; Rodríguez-Antona C; Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.; Lundeberg J; Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, Department of Gene Technology, KTH Royal Institute of Technology, Solna, Sweden.; Gréen H; Clinical Pharmacology, Division of Drug Research, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden; Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, Department of Gene Technology, KTH Royal Institute of Technology, Solna, Sweden; Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden. Electronic address: henrik.green@liu.se.
Source
Publisher: Elsevier Scientific Publishers Country of Publication: Ireland NLM ID: 8800805 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1872-8332 (Electronic) Linking ISSN: 01695002 NLM ISO Abbreviation: Lung Cancer Subsets: MEDLINE
Subject
Language
English
Abstract
Objectives: Gemcitabine/carboplatin treatment is known to cause severe adverse drug reactions which can lead to the need for reduction or cessation of chemotherapy. It would be beneficial to identify patients at risk of severe hematological toxicity in advance before treatment start. This study aims to identify genetic markers for gemcitabine/carboplatin-induced leukopenia and neutropenia in non-small cell lung cancer patients.
Material and Methods: Whole-exome sequencing was performed on 215 patients. Association analysis was performed on single-nucleotide variants (SNVs) and genes, and the validation was based on an independent genome-wide association study (GWAS). Based on the association and validation analyses the genetic variants were then selected for and used in weighted genetic risk score (wGRS) prediction models for leukopenia and neutropenia.
Results: Association analysis identified 50 and 111 SNVs, and 12 and 20 genes, for leukopenia and neutropenia, respectively. Of these SNVS 20 and 19 were partially validated for leukopenia and neutropenia, respectively. The genes SVIL (p = 2.48E-06) and EFCAB2 (p = 4.63E-06) were significantly associated with leukopenia contain the partially validated SNVs rs3740003, rs10160013, rs1547169, rs10927386 and rs10927387. The wGRS prediction models showed significantly different risk scores for high and low toxicity patients.
Conclusion: We have identified and partially validated genetic biomarkers in SNVs and genes correlated to gemcitabine/carboplatin-induced leukopenia and neutropenia and created wGRS models for predicting the risk of chemotherapy-induced hematological toxicity. These results provide a strong foundation for further studies of chemotherapy-induced toxicity.
(Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)
Material and Methods: Whole-exome sequencing was performed on 215 patients. Association analysis was performed on single-nucleotide variants (SNVs) and genes, and the validation was based on an independent genome-wide association study (GWAS). Based on the association and validation analyses the genetic variants were then selected for and used in weighted genetic risk score (wGRS) prediction models for leukopenia and neutropenia.
Results: Association analysis identified 50 and 111 SNVs, and 12 and 20 genes, for leukopenia and neutropenia, respectively. Of these SNVS 20 and 19 were partially validated for leukopenia and neutropenia, respectively. The genes SVIL (p = 2.48E-06) and EFCAB2 (p = 4.63E-06) were significantly associated with leukopenia contain the partially validated SNVs rs3740003, rs10160013, rs1547169, rs10927386 and rs10927387. The wGRS prediction models showed significantly different risk scores for high and low toxicity patients.
Conclusion: We have identified and partially validated genetic biomarkers in SNVs and genes correlated to gemcitabine/carboplatin-induced leukopenia and neutropenia and created wGRS models for predicting the risk of chemotherapy-induced hematological toxicity. These results provide a strong foundation for further studies of chemotherapy-induced toxicity.
(Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)