title: Carboplatin/taxane-induced gastrointestinal toxicity: a pharmacogenomics study on the SCOTROC1 trial.
abstract: Carboplatin/taxane combination is first-line therapy for ovarian cancer. However, patients can encounter treatment delays, impaired quality of life, even death because of chemotherapy-induced gastrointestinal (GI) toxicity. A candidate gene study was conducted to assess potential association of genetic variants with GI toxicity in 808 patients who received carboplatin/taxane in the Scottish Randomized Trial in Ovarian Cancer 1 (SCOTROC1). Patients were randomized into discovery and validation cohorts consisting of 404 patients each. Clinical covariates and genetic variants associated with grade III/IV GI toxicity in discovery cohort were evaluated in replication cohort. Chemotherapy-induced GI toxicity was significantly associated with seven single-nucleotide polymorphisms in the ATP7B, GSR, VEGFA and SCN10A genes. Patients with risk genotypes were at 1.53 to 18.01 higher odds to develop carboplatin/taxane-induced GI toxicity (P<0.01). Variants in the VEGF gene were marginally associated with survival time. Our data provide potential targets for modulation/inhibition of GI toxicity in ovarian cancer patients.
authors.affiliation: Department of Clinical Pharmacology, Xiang-Ya Hospital, Central South University, Changsha, China.|Pharmacogenetics Research institute, Central South University, Changsha, China.|Institute for Pharmacogenomics and Individualized Therapy, University of North Carolina, Chapel Hill, NC, USA.|Moffitt Cancer Center, DeBartolo Family Personalized Medicine Institute, Tampa, FL, USA.
authors.forename: Y J
authors.initials: YJ
authors.lastname: He
authors.affiliation: Bioinformatics Research Center, Department of Statistics, North Carolina State University, Raleigh, NC, USA.|Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
authors.forename: S J
authors.initials: SJ
authors.lastname: Winham
authors.affiliation: Institute for Pharmacogenomics and Individualized Therapy, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Hoskins
authors.affiliation: Institute for Pharmacogenomics and Individualized Therapy, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: S
authors.initials: S
authors.lastname: Glass
authors.affiliation: Cancer Research UK Clinical Trials Unit, Beatson West of Scotland Cancer Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
authors.forename: J
authors.initials: J
authors.lastname: Paul
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London, UK.
authors.forename: R
authors.initials: R
authors.lastname: Brown
authors.affiliation: Bioinformatics Research Center, Department of Statistics, North Carolina State University, Raleigh, NC, USA.
authors.forename: A
authors.initials: A
authors.lastname: Motsinger-Reif
authors.affiliation: Department of Clinical Pharmacology, Xiang-Ya Hospital, Central South University, Changsha, China.|Pharmacogenetics Research institute, Central South University, Changsha, China.|Institute for Pharmacogenomics and Individualized Therapy, University of North Carolina, Chapel Hill, NC, USA.|Moffitt Cancer Center, DeBartolo Family Personalized Medicine Institute, Tampa, FL, USA.
authors.forename: H L
authors.initials: HL
authors.lastname: McLeod
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects*; D016190:Carboplatin / Q000009:adverse effects*; D027682:Cation Transport Proteins / Q000235:genetics; D000073840:Copper-Transporting ATPases; D000077143:Docetaxel; D005260:Female; D005767:Gastrointestinal Diseases / Q000139:chemically induced* / Q000175:diagnosis / Q000235:genetics*; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D053208:Kaplan-Meier Estimate; D062559:NAV1.8 Voltage-Gated Sodium Channel / Q000235:genetics; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000401:mortality; D010597:Pharmacogenetics; D000071184:Pharmacogenomic Variants / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D012307:Risk Factors; D012606:Scotland; D012720:Severity of Illness Index; D043823:Taxoids / Q000009:adverse effects*; D013997:Time Factors; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
chemical_list: D027682:Cation Transport Proteins; D062559:NAV1.8 Voltage-Gated Sodium Channel; C568317:SCN10A protein, human; D043823:Taxoids; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000077143:Docetaxel; D016190:Carboplatin; D000251:Adenosine Triphosphatases; C000612464:ATP7B protein, human; D000073840:Copper-Transporting ATPases