title: Pharmacogenetics of oxaliplatin as adjuvant treatment in colon carcinoma: are single nucleotide polymorphisms in GSTP1, ERCC1, and ERCC2 good predictive markers?
abstract: OBJECTIVE
  Adjuvant chemotherapy improves survival in stage III colon cancer patients. However, a subgroup of patients still develops recurrent disease at some point in time, partly because of the ineffectiveness of the chemotherapy. Predictive markers of response are therefore crucial. Our aim was to study the predictive value of functional polymorphisms in genes involved in the metabolism of oxaliplatin and in DNA repair in stage III colon cancer patients.
  
  
  METHODS
  Normal DNA was isolated from 98 patients diagnosed with stage III colon carcinoma. Single nucleotide polymorphisms (SNPs) in three genes (the excision repair cross-complementing genes ERCC1 [19007T>C] and ERCC2 [2251A>C], and the glutathione S-transferase pi 1 gene [GSTP1 313A>G]) were tested by PCR followed by digestion with restriction enzymes or by direct sequencing. These genes and SNPs were selected on the basis of their reported associations with oxaliplatin response in colorectal cancer.
  
  
  RESULTS
  The genotype frequencies were in Hardy-Weinberg equilibrium. GSTP1 and ERCC2 polymorphisms were significantly associated with sex. The AA genotype of GSTP1 313A>G was more frequent in men than in women (59% vs 30%, p = 0.02), and the CC genotype of ERCC2 2251A>C was significantly more frequent in women than in men (24% vs 6%, p = 0.02). In univariate and multivariate survival analysis, none of the tested polymorphisms seemed to influence disease-free survival. The GSTP1 AA genotype had different effects on survival between men and women; homozygous A men had significantly worse cancer-specific survival and overall survival than women with the same genotype (log rank p = 0.029 and p = 0.015, respectively).
  
  
  CONCLUSIONS
  None of the tested polymorphisms is likely to be a reliable marker of response to oxaliplatin therapy. The GSTP1 313A>G homozygous A genotype may have a prognostic value in male patients.
authors.affiliation: PAMM Laboratory for Pathology, Eindhoven, the Netherlands.
authors.forename: Arantza
authors.initials: A
authors.lastname: Fariña Sarasqueta
authors.forename: Gesina
authors.initials: G
authors.lastname: van Lijnschoten
authors.forename: Valery E P P
authors.initials: VE
authors.lastname: Lemmens
authors.forename: Harm J T
authors.initials: HJ
authors.lastname: Rutten
authors.forename: Adriaan J C
authors.initials: AJ
authors.lastname: van den Brule
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D017024:Chemotherapy, Adjuvant; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D004720:Endonucleases / Q000235:genetics*; D005260:Female; D051549:Glutathione S-Transferase pi / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000627:therapeutic use*; D000077150:Oxaliplatin; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D051759:Xeroderma Pigmentosum Group D Protein / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; C071447:ERCC1 protein, human; D004720:Endonucleases; D051759:Xeroderma Pigmentosum Group D Protein; C497292:ERCC2 protein, human