title: Pharmacogenetic predictors of severe peripheral neuropathy in colon cancer patients treated with oxaliplatin-based adjuvant chemotherapy: a GEMCAD group study.
abstract: BACKGROUND
  Oxaliplatin-based chemotherapy (CT), widely used as adjuvant therapy for stage III and selected high-risk stage II colon cancer (CC) patients, is often associated with cumulative peripheral neuropathy. Our aim is to identify single-nucleotide polymorphisms (SNPs) in genes involved in oxaliplatin metabolism, DNA repair mechanisms, cell cycle control, detoxification or excretion pathways to predict severe (grade 2-3) oxaliplatin-induced peripheral neuropathy (OXPN) among CC patients treated with oxaliplatin and fluoropyrimidine-based adjuvant CT.
  
  
  METHODS
  Genomic DNA was extracted from formalin-fixed-paraffin-embedded peritumoral samples from 206 high-risk stage II and stage III CC patients receiving oxaliplatin-based adjuvant CT from January 2004 to December 2009. Genotyping was carried out for 34 SNPs in 15 genes using MassARRAY (SEQUENOM) technology. A total of 181 stage II-III CC patients treated with the same CT regimens were enrolled as a validation set.
  
  
  RESULTS
  The rs2230641 cyclin H (CCNH) rs2230641 C/C [odd ratio (OR)=5.03, 95% confidence interval (CI) 1.061-2.41, P=0.042] and the ATP-binding cassette subfamily G, member 2 (ABCG2) rs3114018 A/A genotypes (OR=2.67; 95% CI 0.95-4.41; P=0.059) were associated with a higher risk of severe OXPN. In addition, patients harboring the combination of CCNH C/C and/or the ABCG2 rs3114018 A/A genotypes had a higher risk of grade 2-3 OXPN than those with the CCNH any T and ABCG2 any C genotypes (37.73% versus 19.42%; OR=2.46; 95% CI 1.19-5.07; P=0.014) in the logistic regression analysis using age, gender, adjuvant CT regimen and cumulative dose of oxaliplatin as covariates. The ability to predict severe OXPN of this combined analysis was independently validated in the second cohort (58% versus 33.33%; OR=2.99; 95% CI 1.45-6.13; P=0.002).
  
  
  CONCLUSIONS
  Our results suggest that SNPs in CCNH and ABCG2 can modulate the development of severe OXPN among stage II-III CC patients who received oxaliplatin-based CT, thus enabling the individualization of adjuvant treatment.
authors.affiliation: Department of Medical Oncology, La Paz Universitary Hospital, IdiPaz, Madrid.
authors.forename: A
authors.initials: A
authors.lastname: Custodio
authors.forename: J
authors.initials: J
authors.lastname: Moreno-Rubio
authors.forename: J
authors.initials: J
authors.lastname: Aparicio
authors.forename: J
authors.initials: J
authors.lastname: Gallego-Plazas
authors.forename: R
authors.initials: R
authors.lastname: Yaya
authors.forename: J
authors.initials: J
authors.lastname: Maurel
authors.forename: O
authors.initials: O
authors.lastname: Higuera
authors.forename: E
authors.initials: E
authors.lastname: Burgos
authors.forename: D
authors.initials: D
authors.lastname: Ramos
authors.forename: A
authors.initials: A
authors.lastname: Calatrava
authors.forename: E
authors.initials: E
authors.lastname: Andrada
authors.forename: R
authors.initials: R
authors.lastname: López
authors.forename: V
authors.initials: V
authors.lastname: Moreno
authors.forename: R
authors.initials: R
authors.lastname: Madero
authors.forename: P
authors.initials: P
authors.lastname: Cejas
authors.forename: J
authors.initials: J
authors.lastname: Feliu
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000627:therapeutic use; D017024:Chemotherapy, Adjuvant; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D056748:Cyclin H / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics*; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012189:Retrospective Studies; D055815:Young Adult
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C534751:CCNH protein, human; D056748:Cyclin H; D009363:Neoplasm Proteins; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin
keywords: adjuvant chemotherapy; colon cancer; early-stage; oxaliplatin; peripheral neuropathy; single-nucleotide polymorphism