Explorative study to identify novel candidate genes related to oxaliplatin efficacy and toxicity using a DNA repair array

• Published in: British journal of cancer Vol. 101; no. 2; pp. 357 - 362
• Main Authors: Kweekel, D M, Antonini, N F, Nortier, J W R, Punt, C J A, Gelderblom, H, Guchelaar, H-J
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21.07.2009; Nature Publishing Group
• Subjects: Antineoplastic Agents - adverse effects; Antineoplastic Agents - pharmacology; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Ataxia Telangiectasia Mutated Proteins; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Camptothecin - administration & dosage; Camptothecin - adverse effects; Camptothecin - analogs & derivatives; Cancer Research; Cancer therapies; Capecitabine; Cell Cycle Proteins - genetics; Colorectal cancer; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Cyclin-dependent kinases; Deoxycytidine - administration & dosage; Deoxycytidine - adverse effects; Deoxycytidine - analogs & derivatives; Disease-Free Survival; DNA repair; DNA Repair - genetics; DNA, Neoplasm - blood; DNA, Neoplasm - genetics; DNA-Binding Proteins - genetics; Drug dosages; Drug Resistance; Endonucleases - genetics; Epidemiology; Fluorouracil - administration & dosage; Fluorouracil - adverse effects; Fluorouracil - analogs & derivatives; Genes; Genetics and Genomics; Genomes; Hematology; Humans; Kinases; Medical research; Medical sciences; Molecular Medicine; Neurotoxicity; Nuclear Proteins - genetics; Oncology; Organoplatinum Compounds - administration & dosage; Organoplatinum Compounds - adverse effects; Organoplatinum Compounds - pharmacology; Polymorphism, Single Nucleotide; Protein-Serine-Threonine Kinases - genetics; Toxicity; Transcription Factors - genetics; Tumor Suppressor Proteins - genetics; Tumors; Netherlands; toxicity; oxaliplatin; SNP array; efficacy; Antineoplastic agent; Toxicity; Treatment efficiency; ERCC5 gene; DNA repair; Repair gene; Alkylating agent; Cancerology; Oxaliplatin; DNA; Candidate gene; ATM; ERCC5; Platinum II Complexes; Tumor suppressor gene
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/sj.bjc.6605134

Purpose: To identify new polymorphisms (single nucleotide polymorphisms, SNPs) in DNA repair pathways that are associated with efficacy and toxicity in patients receiving oxaliplatin and capecitabine for advanced colorectal cancer (ACC). Methods: We studied progression-free survival (PFS) in 91 ACC patients, of whom germ-line DNA was isolated and genotyped using an Asper Biotech array. Overall survival (OS) and toxicity were studied as secondary end points. A step-wise selection of SNPs was performed, involving univariate and multivariate log-rank tests and Cox regression analysis, with age and performance status as covariates. Results: A total of 81 SNPs in 46 genes on the array were selected for further analysis, based on genotyping success rates and minor allele frequencies. After step-wise selection, we found that homozygosity for the ataxia telangiectasia mutated gene ( ATM ) rs1801516 or excision repair cross-complementing gene ( ERCC5 ) rs1047768 SNPs was associated with shorter PFS; however there were no significant associations ( P >0.01) with OS or toxicity. Discussion: This is the first study describing the pathway gene approach for the selection of new candidate genes involved in oxaliplatin efficacy and toxicity. The results suggest that the ATM and ERCC5 genes may be associated with oxaliplatin efficacy in ACC.