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Pharmacogenomics J. 2014 Apr;14(2):142-50. doi: 10.1038/tpj.2013.20. Epub 2013 Jul 2.

Association of common gene variants in the WNT/β-catenin pathway with colon cancer recurrence.

Author information

  • 11] Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA [2] Department of Medical Oncology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
  • 21] Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA [2] Division of Clinical Oncology, Research Unit Genetic Epidemiology and Pharmacogenetics, Department of Internal Medicine, Medical University of Graz, Graz, Austria.
  • 3Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • 4Department of Preventive Medicine, Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
  • 51] Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA [2] Department of Biology and Chemistry, Azusa Pacific University, Azusa, CA, USA.
  • 61] Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA [2] University of Southern California, Center for Molecular Pathways and Drug Discovery, Keck School of Medicine, Los Angeles, CA, USA.

Abstract

Wnt/β-catenin signaling has a central role in the development and progression of most colon cancers (CCs). Germline variants in Wnt/β-catenin pathway genes may result in altered gene function and/or activity, thereby causing inter-individual differences in relation to tumor recurrence capacity and chemoresistance. We investigated germline polymorphisms in a comprehensive panel of Wnt/β-catenin pathway genes to predict time to tumor recurrence (TTR) in patients with stage III and high-risk stage II CC. A total of 234 patients treated with 5-fluorouracil-based chemotherapy were included in this study. Whole-blood samples were analyzed for putative functional germline polymorphisms in SFRP3, SFRP4, DKK2, DKK3, Axin2, APC, TCF7L2, WNT5B, CXXC4, NOTCH2 and GLI1 genes by PCR-based restriction fragment-length polymorphism or direct DNA sequencing. Polymorphisms with statistical significance were validated in an independent study cohort. The minor allele of WNT5B rs2010851 T>G was significantly associated with a shorter TTR (10.7 vs 4.9 years; hazard ratio: 2.48; 95% CI, 0.96-6.38; P=0.04) in high-risk stage II CC patients. This result remained significant in multivariate Cox's regression analysis. This study shows that the WNT5B germline variant rs2010851 was significantly identified as a stage-dependent prognostic marker for CC patients after 5-fluorouracil-based adjuvant therapy.

PMID:
23817222
DOI:
10.1038/tpj.2013.20
[PubMed - indexed for MEDLINE]
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