Genetics and Genomics

British Journal of Cancer (2009) 101, 357–362. doi:10.1038/sj.bjc.6605134 www.bjcancer.com
Published online 16 June 2009

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

D M Kweekel1, N F Antonini2, J W R Nortier3, C J A Punt4, H Gelderblom3 and H-J Guchelaar1

  1. 1Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands
  2. 2Biometrics Department, Netherlands Cancer Institute (NKI), Amsterdam, The Netherlands
  3. 3Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands
  4. 4Department of Oncology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands

Correspondence: Dr DM Kweekel, E-mail: d.m.kweekel@lumc.nl

Received 5 February 2009; Revised 14 May 2009; Accepted 21 May 2009; Published online 16 June 2009.

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Abstract

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.

Keywords:

SNP array, oxaliplatin, efficacy, toxicity, ATM, ERCC5