title: Cumulative genetic risk predicts platinum/taxane-induced neurotoxicity.
abstract: OBJECTIVE
  The combination of a platinum and taxane are standard of care for many cancers, but the utility is often limited due to debilitating neurotoxicity. We examined whether single-nucleotide polymorphisms (SNP) from annotated candidate genes will identify genetic risk for chemotherapy-induced neurotoxicity.
  
  
  METHODS
  A candidate-gene association study was conducted to validate the relevance of 1,261 SNPs within 60 candidate genes in 404 ovarian cancer patients receiving platinum/taxane chemotherapy on the SCOTROC1 trial. Statistically significant variants were then assessed for replication in a separate 404 patient replication cohort from SCOTROC1.
  
  
  RESULTS
  Significant associations with chemotherapy-induced neurotoxicity were identified and replicated for four SNPs in SOX10, BCL2, OPRM1, and TRPV1. The population attributable risk for each of the four SNPs ranged from 5% to 35%, with a cumulative risk of 62%. According to the multiplicative model, the odds of developing neurotoxicity increase by a factor of 1.64 for every risk genotype. Patients possessing three risk variants have an estimated OR of 4.49 (2.36-8.54) compared to individuals with 0 risk variants. Neither the four SNPs nor the risk score were associated with progression-free survival or overall survival.
  
  
  CONCLUSIONS
  This study shows that SNPs in four genes have a significant cumulative association with increased risk for the development of chemotherapy-induced neurotoxicity, independent of patient survival.
authors: Authors' Affiliations: Schools of Pharmacy and Medicine; Institute for Pharmacogenomics and Individualized Therapy, University of North Carolina, Chapel Hill; Bioinformatics Research Center and Department of Statistics, North Carolina State University; The Beatson Oncology Centre, University of Glasgow, Glasgow; and Department of Oncology, Imperial College London, London, United Kingdom.
authors: Sarah
authors: S
authors: McWhinney-Glass
authors: Stacey J
authors: SJ
authors: Winham
authors: Daniel L
authors: DL
authors: Hertz
authors: Jane
authors: J
authors: Yen Revollo
authors: Jim
authors: J
authors: Paul
authors: Yijing
authors: Y
authors: He
authors: Robert
authors: R
authors: Brown
authors: Alison A
authors: AA
authors: Motsinger-Reif
authors: Howard L
authors: HL
authors: McLeod
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D001952:Bridged-Ring Compounds / Q000009:adverse effects* / Q000627:therapeutic use; D016022:Case-Control Studies; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D009422:Nervous System Diseases / Q000139:chemically induced* / Q000235:genetics*; D016017:Odds Ratio; D010051:Ovarian Neoplasms / Q000150:complications* / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D010984:Platinum / Q000009:adverse effects* / Q000627:therapeutic use; D020641:Polymorphism, Single Nucleotide; D043823:Taxoids / Q000009:adverse effects* / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D001952:Bridged-Ring Compounds; D043823:Taxoids; C080625:taxane; D010984:Platinum
references: Clin Cancer Res. 2006 May 15;12(10):3050-6
references: 16707601
references: Curr Pain Headache Rep. 2006 Aug;10(4):279-87
references: 16834943
references: Pflugers Arch. 2012 Apr;463(4):561-9
references: 22258694
references: Nature. 2010 Sep 2;467(7311):52-8
references: 20811451
references: Anticancer Drugs. 2009 Jun;20(5):396-402
references: 19287306
references: Ann Oncol. 2013 Feb;24(2):454-462
references: 22910842
references: Breast Cancer Res Treat. 2012 Jul;134(1):401-10
references: 22527101
references: Nat Genet. 2006 Aug;38(8):904-9
references: 16862161
references: N Engl J Med. 2008 Sep 25;359(13):1367-80
references: 18815398
references: J Clin Oncol. 2007 Sep 1;25(25):4028-9
references: 17664456
references: J Natl Cancer Inst. 2004 Nov 17;96(22):1682-91
references: 15547181
references: Lancet Oncol. 2006 Apr;7(4):288
references: 16598880
references: Clin Cancer Res. 2012 Sep 15;18(18):5099-109
references: 22843789
references: J Clin Oncol. 2012 Sep 1;30(25):3051-7
references: 22851566
references: J Clin Oncol. 2007 Apr 1;25(10):1247-54
references: 17401013
references: N Engl J Med. 2010 Sep 2;363(10):943-53
references: 20818904
references: J Clin Oncol. 2007 Oct 10;25(29):4528-35
references: 17925548
references: Nat Rev Genet. 2006 Aug;7(8):632-44
references: 16847463
references: Am J Public Health. 1995 Sep;85(9):1202-4
references: 7661224
references: N Engl J Med. 2011 Mar 24;364(12):1144-53
references: 21428770
references: Br J Cancer. 2011 Jul 26;105(3):360-5
references: 21750553
references: Mol Cancer Ther. 2009 Jan;8(1):10-6
references: 19139108
references: Pharmacogenet Genomics. 2009 Jul;19(7):563-4
references: 19525887
references: J Clin Oncol. 2007 Oct 10;25(29):4513-5
references: 17925544
references: N Engl J Med. 2004 Oct 7;351(15):1502-12
references: 15470213
references: Support Care Cancer. 2011 Nov;19(11):1769-77
references: 20936417