title: A multivariate analysis of genomic polymorphisms: prediction of clinical outcome to 5-FU/oxaliplatin combination chemotherapy in refractory colorectal cancer.
abstract: In this marker evaluation study, we tested whether distinct patterns of functional genomic polymorphisms in genes involved in drug metabolic pathways and DNA repair that predict clinical outcome to 5-fluorouracil (5-FU)/oxaliplatin chemotherapy in patients with advanced colorectal cancer could be identified. Functional polymorphisms in DNA-repair genes XPD, ERCC1, XRCC1, XPA, and metabolising genes glutathione S-transferase GSTP1, GSTT1, GSTM1, and thymidylate synthase (TS) were assessed retrospectively in 106 patients with refractory stage IV disease who received 5-FU/oxaliplatin combination chemotherapy, using a polymerase chain reaction-based RFLP technique. Favourable genotypes from polymorphisms in XPD-751, ERCC1-118, GSTP1-105, and TS-3'-untranslated region (3'UTR) that are associated with overall survival were identified. After adjustment for performance status, the relative risks of dying for patients who possessed the unfavourable genotype were: 3.33 for XPD-751 (P=0.037), 3.25 for GSTP1-105 (P=0.072), 2.05 for ERCC1-118 (P=0.037), and 1.65 for TS-3'UTR (P=0.091) when compared to their respective beneficial genomic variants. Combination analysis with all four polymorphisms revealed that patients possessing > or =2 favourable genotypes survived a median of 17.4 months (95% confidence interval (CI): 9.4, 26.5) compared to 5.4 months (95% CI: 4.3, 6.0) in patients with no favourable genotype. Patients who carried one favourable genotype demonstrated intermediate survival of 10.2 months (95% CI: 6.8, 15.3; P<0.001). Polymorphisms in the TS-3'UTR and GSTP1-105 gene were also associated with time to progression. After adjustment for performance status, patients with an unfavourable TS-3'UTR genotype had a relative risk of disease progression of 1.76 (P=0.020) and those with the unfavourable GSTP1-105 genotype showed a relative risk of progression of 2.00 (P=0.018). The genomic polymorphisms XPD-751, ERCC1-118, GSTP1-105, and TS-3'UTR may be useful in predicting overall survival and time to progression of colorectal cancer in patients who receive 5-FU/oxaliplatin chemotherapy. These findings require independent prospective confirmation.
authors.affiliation: Department of Hematology and Oncology, University of Hamburg, University Hospital, Hamburg 20247, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Stoehlmacher
authors.forename: D J
authors.initials: DJ
authors.lastname: Park
authors.forename: W
authors.initials: W
authors.lastname: Zhang
authors.forename: D
authors.initials: D
authors.lastname: Yang
authors.forename: S
authors.initials: S
authors.lastname: Groshen
authors.forename: S
authors.initials: S
authors.lastname: Zahedy
authors.forename: H-J
authors.initials: HJ
authors.lastname: Lenz
mesh_terms: D000217:Acyltransferases / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D004265:DNA Helicases; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics; D018450:Disease Progression; D004720:Endonucleases / Q000235:genetics; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D015972:Gene Expression Regulation, Neoplastic; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D011110:Polymorphism, Genetic / Q000235:genetics*; D011237:Predictive Value of Tests; D011506:Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D013940:Thymidylate Synthase / Q000235:genetics; D013997:Time Factors; D014157:Transcription Factors; D016896:Treatment Outcome; D000076105:X-ray Repair Cross Complementing Protein 1; D051760:Xeroderma Pigmentosum Group A Protein; D051759:Xeroderma Pigmentosum Group D Protein
chemical_list: D000217:Acyltransferases; D014408:Biomarkers, Tumor; D004265:DNA Helicases; D004268:DNA-Binding Proteins; D004720:Endonucleases; D005472:Fluorouracil; D005982:Glutathione Transferase; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D011506:Proteins; D012333:RNA, Messenger; D013940:Thymidylate Synthase; D014157:Transcription Factors; D000076105:X-ray Repair Cross Complementing Protein 1; D051760:Xeroderma Pigmentosum Group A Protein; D051759:Xeroderma Pigmentosum Group D Protein; C497314:XPA protein, human; C000619371:XRCC1 protein, human; C413545:glutathione S-transferase T1; C071447:ERCC1 protein, human; C043403:fatty acyl ethyl ester synthase; C497292:ERCC2 protein, human