title: Using Whole-Exome Sequencing to Identify Genetic Markers for Carboplatin and Gemcitabine-Induced Toxicities.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Science for Life Laboratory, School of Biotechnology, Division of Gene Technology, Royal Institute of Technology, Solna, Sweden. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden. Division of Drug Research, Clinical Pharmacology, Department of Medical and Health Sciences, Linköping University, Linköping, Sweden. henrik.green@liu.se.
authors.forename: Henrik
authors.initials: H
authors.lastname: Gréen
authors.affiliation: Science for Life Laboratory, School of Biotechnology, Division of Gene Technology, Royal Institute of Technology, Solna, Sweden.
authors.forename: Johanna
authors.initials: J
authors.lastname: Hasmats
authors.affiliation: Science for Life Laboratory, School of Biotechnology, Division of Gene Technology, Royal Institute of Technology, Solna, Sweden. NextBio, Cupertino, California.
authors.forename: Ilya
authors.initials: I
authors.lastname: Kupershmidt
authors.affiliation: Science for Life Laboratory, School of Biotechnology, Division of Gene Technology, Royal Institute of Technology, Solna, Sweden.
authors.forename: Daniel
authors.initials: D
authors.lastname: Edsgärd
authors.affiliation: Department of Oncology and Pathology, Karolinska Institute and Oncology Clinic, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Luigi
authors.initials: L
authors.lastname: de Petris
authors.affiliation: Department of Oncology and Pathology, Karolinska Institute and Oncology Clinic, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Rolf
authors.initials: R
authors.lastname: Lewensohn
authors.affiliation: Department of Medical Oncology, Christie Hospital, Manchester, United Kingdom. Institute of Cancer Sciences, University of Manchester, Manchester, United Kingdom.
authors.forename: Fiona
authors.initials: F
authors.lastname: Blackhall
authors.affiliation: Division of Drug Research, Clinical Pharmacology, Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.
authors.forename: Svante
authors.initials: S
authors.lastname: Vikingsson
authors.affiliation: Unité INSERM U 981, Université Paris Sud, Département de Médecine, Institut Gustave Roussy, Villejuif, France.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Besse
authors.affiliation: Department of Clinical Physiology, University Hospital, Linköping, Sweden. Department of Medical and Health Sciences, Linköping University, Linköping, Sweden. Department of Pulmonary Medicine, University Hospital, Linköping, Sweden.
authors.forename: Andrea
authors.initials: A
authors.lastname: Lindgren
authors.affiliation: Department of Oncology and Pathology, Karolinska Institute and Oncology Clinic, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Eva
authors.initials: E
authors.lastname: Brandén
authors.affiliation: Department of Oncology and Pathology, Karolinska Institute and Oncology Clinic, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Hirsh
authors.initials: H
authors.lastname: Koyi
authors.affiliation: Division of Drug Research, Clinical Pharmacology, Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.
authors.forename: Curt
authors.initials: C
authors.lastname: Peterson
authors.affiliation: Science for Life Laboratory, School of Biotechnology, Division of Gene Technology, Royal Institute of Technology, Solna, Sweden.
authors.forename: Joakim
authors.initials: J
authors.lastname: Lundeberg
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D016190:Carboplatin / Q000009:adverse effects* / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics; D003841:Deoxycytidine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D064420:Drug-Related Side Effects and Adverse Reactions / Q000235:genetics*; D059472:Exome / Q000235:genetics*; D005260:Female; D005819:Genetic Markers / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D013921:Thrombocytopenia / Q000139:chemically induced; D000093542:Gemcitabine
chemical_list: D005819:Genetic Markers; D003841:Deoxycytidine; D016190:Carboplatin; D000093542:Gemcitabine