SNPs in transporter and metabolizing genes as predictive markers for oxaliplatin treatment in colorectal cancer patients

Int J Cancer. 2016 Jun 15;138(12):2993-3001. doi: 10.1002/ijc.30026. Epub 2016 Feb 19.


Oxaliplatin is frequently used as part of a chemotherapeutic regimen with 5-fluorouracil in the treatment of colorectal cancer (CRC). The cellular availability of oxaliplatin is dependent on metabolic and transporter enzymes. Variants in genes encoding these enzymes may cause variation in response to oxaliplatin and could be potential predictive markers. Therefore, we used a two-step procedure to comprehensively investigate 1,444 single nucleotide polymorphisms (SNPs) from these pathways for their potential as predictive markers for oxaliplatin treatment, using 623 stage II-IV CRC patients (of whom 201 patients received oxaliplatin) from a German prospective patient cohort treated with adjuvant or palliative chemotherapy. First, all genes were screened using the global test that evaluated SNP*oxaliplatin interaction terms per gene. Second, one model was created by backward elimination on all SNP*oxaliplatin interactions of the selected genes. The statistical procedure was evaluated using bootstrap analyses. Nine genes differentially associated with overall survival according to oxaliplatin treatment (unadjusted p values < 0.05) were selected. Model selection resulted in the inclusion of 14 SNPs from eight genes (six transporter genes, ABCA9, ABCB11, ABCC10, ATP1A1, ATP1B2, ATP8B3, and two metabolism genes GSTM5, GRHPR), which significantly improved model fit. Using bootstrap analysis we show an improvement of the prediction error of 3.7% in patients treated with oxaliplatin. Several variants in genes involved in metabolism and transport could thus be potential predictive markers for oxaliplatin treatment in CRC patients. If confirmed, inclusion of these variants in a predictive test could identify patients who are more likely to benefit from treatment with oxaliplatin.

Keywords: colorectal cancer; metabolism; oxaliplatin; predictive markers; transport.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP-Binding Cassette Transporters / genetics
  • Adenosine Triphosphatases / genetics
  • Aged
  • Aged, 80 and over
  • Alcohol Oxidoreductases / genetics
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Biomarkers, Tumor / genetics*
  • Case-Control Studies
  • Colorectal Neoplasms / drug therapy
  • Colorectal Neoplasms / genetics*
  • Drug Resistance, Neoplasm / genetics
  • Female
  • Fluorouracil / pharmacology
  • Fluorouracil / therapeutic use
  • Gene Frequency
  • Genetic Association Studies
  • Humans
  • Leucovorin / pharmacology
  • Leucovorin / therapeutic use
  • Male
  • Middle Aged
  • Organoplatinum Compounds / administration & dosage
  • Organoplatinum Compounds / pharmacology
  • Organoplatinum Compounds / therapeutic use
  • Oxaliplatin
  • Polymorphism, Single Nucleotide*
  • Prospective Studies
  • Treatment Outcome


  • ATP-Binding Cassette Transporters
  • Biomarkers, Tumor
  • Organoplatinum Compounds
  • Oxaliplatin
  • Alcohol Oxidoreductases
  • glyoxylate reductase
  • Adenosine Triphosphatases
  • Leucovorin
  • Fluorouracil

Supplementary concepts

  • Folfox protocol