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

The Pharmacogenomics Journal volume 14, pages 142–150 (2014)Cite this article

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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.

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Acknowledgements

This work was supported by the National Institutes of Health (grant number P30CA) and the Danny Butler Research Fund. DP is the recipient of a fellowship from the Instituto de Salud Carlos III (CM08/00065).

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Authors and Affiliations

  1. Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    D Páez, A Gerger, W Zhang, M J Labonte, L Benhanim, M Kahn, F Lenz, C Lenz, Y Ning, T Wakatsuki, F Loupakis & H-J Lenz

  2. Department of Medical Oncology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain

    D Páez

  3. Division of Clinical Oncology, Department of Internal Medicine, Research Unit Genetic Epidemiology and Pharmacogenetics, Medical University of Graz, Graz, Austria

    A Gerger

  4. Department of Preventive Medicine, Norris Comprehensive Cancer Center, Los Angeles, CA, USA

    D Yang

  5. Department of Biology and Chemistry, Azusa Pacific University, Azusa, CA, USA

    M J Labonte

  6. University of Southern California, Center for Molecular Pathways and Drug Discovery, Keck School of Medicine, Los Angeles, CA, USA

    H-J Lenz

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  1. D Páez
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Páez, D., Gerger, A., Zhang, W. et al. Association of common gene variants in the WNT/β-catenin pathway with colon cancer recurrence. Pharmacogenomics J 14, 142–150 (2014). https://doi.org/10.1038/tpj.2013.20

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