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Using Whole-Exome Sequencing to Identify Genetic Markers for Carboplatin and Gemcitabine-Induced Toxicities
Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Division of Gene Technology, Royal Institute of Technology, Solna, Sweden/ Royal Institute Technology, Sweden; National Board Forens Med, Department Forens Genet and Forens Toxicol, Linkoping, Sweden.
Royal Institute Technology, Sweden.
Royal Institute Technology, Sweden; NextBio, CA USA.
Royal Institute Technology, Sweden.
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2016 (English)In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 22, no 2, 366-373 p.Article in journal (Refereed) PublishedText
Abstract [en]

Purpose: Chemotherapies are associated with significant interindividual variability in therapeutic effect and adverse drug reactions. In lung cancer, the use of gemcitabine and carboplatin induces grade 3 or 4 myelosuppression in about a quarter of the patients, while an equal fraction of patients is basically unaffected in terms of myelosuppressive side effects. We therefore set out to identify genetic markers for gemcitabine/carboplatin-induced myelosuppression. Experimental Design: We exome sequenced 32 patients that suffered extremely high neutropenia and thrombocytopenia (grade 3 or 4 after first chemotherapy cycle) or were virtually unaffected (grade 0 or 1). The genetic differences/polymorphism between the groups were compared using six different bioinformatics strategies: (i) whole-exome nonsynonymous single-nucleotide variants association analysis, (ii) deviation from Hardy-Weinberg equilibrium, (iii) analysis of genes selected by a priori biologic knowledge, (iv) analysis of genes selected from gene expression meta-analysis of toxicity datasets, (v) Ingenuity Pathway Analysis, and (vi) FunCoup network enrichment analysis. Results: A total of 53 genetic variants that differed among these groups were validated in an additional 291 patients and were correlated to the patients myelosuppression. In the validation, we identified rs1453542 in OR4D6 (P = 0.0008; OR, 5.2; 95% CI, 1.8-18) as a marker for gemcitabine/carboplatin-induced neutropenia and rs5925720 in DDX53 (P = 0.0015; OR, 0.36; 95% CI, 0.17-0.71) as a marker for thrombocytopenia. Patients homozygous for the minor allele of rs1453542 had a higher risk of neutropenia, and for rs5925720 the minor allele was associated with a lower risk for thrombocytopenia. Conclusions: We have identified two new genetic markers with the potential to predict myelosuppression induced by gemcitabine/ carboplatin chemotherapy. (C)2015 AACR.

Place, publisher, year, edition, pages
AMER ASSOC CANCER RESEARCH , 2016. Vol. 22, no 2, 366-373 p.
National Category
Medical Genetics Cancer and Oncology
Identifiers
URN: urn:nbn:se:liu:diva-125314DOI: 10.1158/1078-0432.CCR-15-0964ISI: 000369076500013PubMedID: 26378035OAI: oai:DiVA.org:liu-125314DiVA: diva2:906258
Note

Funding Agencies|European Commission [CHEMORES LSHC-CT-2007-037665]; Swedish Cancer Society; Swedish Research Council; Fondkistan; Stiftelsen Sigurd och Elsa Goljes Minne; Marcus Borgstroms stiftelse

Available from: 2016-02-24 Created: 2016-02-19 Last updated: 2016-03-04

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Green, HenrikVikingsson, SvanteLindgren, AndreaPeterson, Curt
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Division of Drug ResearchFaculty of Medicine and Health SciencesDepartment of Medical and Health SciencesDepartment of Clinical Physiology in LinköpingDepartment of Oncology
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Clinical Cancer Research
Medical GeneticsCancer and Oncology

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