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


CONCLUSIONS
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.
Kweekel
D M
DM
Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands. d.m.kweekel@lumc.nl
Antonini
N F
NF
Nortier
J W R
JW
Punt
C J A
CJ
Gelderblom
H
H
Guchelaar
H-J
HJ
D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D064007:Ataxia Telangiectasia Mutated Proteins; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D000069287:Capecitabine; D018797:Cell Cycle Proteins / Q000235:genetics; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics*; D004273:DNA, Neoplasm / Q000097:blood / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D018572:Disease-Free Survival; D004720:Endonucleases / Q000235:genetics; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D006801:Humans; D000077146:Irinotecan; D009687:Nuclear Proteins / Q000235:genetics; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D000077150:Oxaliplatin; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics; D000099250:DNA Excision Repair Protein ERCC-5
D000970:Antineoplastic Agents; D064007:Ataxia Telangiectasia Mutated Proteins; D002166:Camptothecin; D000069287:Capecitabine; D018797:Cell Cycle Proteins; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D003841:Deoxycytidine; D004720:Endonucleases; D005472:Fluorouracil; D000077146:Irinotecan; D009687:Nuclear Proteins; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D017346:Protein Serine-Threonine Kinases; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D000099250:DNA Excision Repair Protein ERCC-5; C576324:ATM protein, human