AGXT and ERCC2 polymorphisms are associated with clinical outcome in metastatic colorectal cancer patients treated with 5-FU/oxaliplatin.
The objective of the study was to investigate whether specific single nucleotide polymorphisms (SNPs) with influence on drug transport, biotransformation and repair mechanisms are associated with treatment outcome and toxicity in metastatic colorectal cancer (mCRC). We genotyped blood samples from 519 mCRC patients treated with first-line 5-fluorouracil and oxaliplatin +/- cetuximab for 17 SNPs in 10 genes involved in membrane transport (ABCC1 and ABCC2), drug biotransformation (GSTP1 and AGXT) and DNA repair (ERCC1, ERCC2, XRCC1, XRCC3, XPG and MSH6). The AGXT-rs34116584 and the ERCC2-rs238406 polymorphisms were significantly associated with progression-free survival (P=0.002 and P=0.001, respectively). Associations between 18 toxicity variables and SNPs were identified, although none were significant after Bonferroni correction for multiple comparisons. The study identified SNPs of potential use as markers of clinical outcome in oxaliplatin-treated mCRC patients. If validated in other studies, they could improve the selection of therapy in mCRC.
Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
J B
JB
Kjersem
Department of Oncology, Oslo University Hospital, Oslo, Norway.
M
M
Thomsen
Department of Oncology, Oslo University Hospital, Oslo, Norway.
T
T
Guren
Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
J
J
Hamfjord
Department of Surgery, Sahlgrenska Academy at University of Gothenburg, Sahlgrenska University Hospital/Östra, Gothenburg, Sweden.
G
G
Carlsson
Department of Surgery, Sahlgrenska Academy at University of Gothenburg, Sahlgrenska University Hospital/Östra, Gothenburg, Sweden.
B
B
Gustavsson
Akershus University Hospital, Lørenskog, Norway.
T
T
Ikdahl
Department of Oncology, Ålesund Hospital, Møre and Romsdal Hospital Trust, Ålesund, Norway.
G
G
Indrebø
Department of Oncology, Odense University Hospital, Sdr Boulevard 29, Odense C, Denmark.
P
P
Pfeiffer
Department of Computer Science, University of Oslo, Oslo, Norway.|K.G. Jebsen Center for Breast Cancer Research, Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
O
O
Lingjærde
Department of Oncology, Oslo University Hospital, Oslo, Norway.
K M
KM
Tveit
Department of Surgery, Sahlgrenska Academy at University of Gothenburg, Sahlgrenska University Hospital/Östra, Gothenburg, Sweden.
Y
Y
Wettergren
Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
E H
EH
Kure
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics*; D017326:Clinical Trials, Phase III as Topic; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects / Q000627:therapeutic use*; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D009362:Neoplasm Metastasis; D009944:Organoplatinum Compounds / Q000009:adverse effects / Q000627:therapeutic use*; D000077150:Oxaliplatin; D000071184:Pharmacogenomic Variants / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D016032:Randomized Controlled Trials as Topic; D012189:Retrospective Studies; D012307:Risk Factors; D012537:Scandinavian and Nordic Countries; D013997:Time Factors; D000637:Transaminases / Q000235:genetics*; D016896:Treatment Outcome; D051759:Xeroderma Pigmentosum Group D Protein / Q000235:genetics*; D055815:Young Adult
C000715087:ABCC2 protein, human; D014408:Biomarkers, Tumor; D000089762:Multidrug Resistance-Associated Protein 2; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D000637:Transaminases; C019635:Alanine-glyoxylate transaminase; D051759:Xeroderma Pigmentosum Group D Protein; C497292:ERCC2 protein, human; D005472:Fluorouracil