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Wnt signaling pathway pharmacogenetics in non-small cell lung cancer

The Pharmacogenomics Journal volume 14, pages 509–522 (2014)Cite this article

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Abstract

Wingless-type protein (Wnt)/β-catenin pathway alterations in non-small cell lung cancer (NSCLC) are associated with poor prognosis and resistance. In 598 stage III–IV NSCLC patients receiving platinum-based chemotherapy at the MD Anderson Cancer Center (MDACC), we correlated survival with 441 host single-nucleotide polymorphisms (SNPs) in 50 Wnt pathway genes. We then assessed the most significant SNPs in 240 Mayo Clinic patients receiving platinum-based chemotherapy for advanced NSCLC, 127 MDACC patients receiving platinum-based adjuvant chemotherapy and 340 early stage MDACC patients undergoing surgery alone (cohorts 2–4). In multivariate analysis, survival correlates with SNPs for AXIN2 (rs11868547 and rs4541111, of which rs11868547 was assessed in cohorts 2–4), Wnt-5B (rs12819505), CXXC4 (rs4413407) and WIF-1 (rs10878232). Median survival was 19.7, 15.6 and 10.7 months for patients with 1, 2 and 3–5 unfavorable genotypes, respectively (P=3.8 × 10−9). Survival tree analysis classified patients into two groups (median survival time 11.3 vs 17.3 months, P=4.7 × 10−8). None of the SNPs achieved significance in cohorts 2–4; however, there was a trend in the same direction as cohort 1 for 3 of the SNPs. Using online databases, we found rs10878232 displayed expression quantitative trait loci correlation with the expression of LEMD3, a neighboring gene previously associated with NSCLC survival. In conclusion, results from cohort 1 provide further evidence for an important role for Wnt in NSCLC. Investigation of Wnt inhibitors in advanced NSCLC would be reasonable. Lack of an SNP association with outcome in cohorts 2–4 could be due to low statistical power, impact of patient heterogeneity or false-positive observations in cohort 1.

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Acknowledgements

This study was supported in part by NIH grants R01 CA111646, P50 CA070907, R01 CA55769, R01-CA80127 and R01-CA84354, and the Mayo Foundation fund.

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Authors and Affiliations

  1. Division of Medical Oncology, University of Ottawa, The Ottawa Hospital, Ottawa, ON, Canada

    D J Stewart

  2. Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    D W Chang, Y Ye, M Spitz, X Shu & X Wu

  3. Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    C Lu

  4. Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, MN, USA

    J A Wampfler & P Yang

  5. Department of Medical Oncology, Mayo Clinic College of Medicine, Rochester, MN, USA

    R S Marks

  6. Department of Radiation Oncology, Mayo Clinic College of Medicine, Rochester, MN, USA

    Y I Garces

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Correspondence to D J Stewart.

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Stewart, D., Chang, D., Ye, Y. et al. Wnt signaling pathway pharmacogenetics in non-small cell lung cancer. Pharmacogenomics J 14, 509–522 (2014). https://doi.org/10.1038/tpj.2014.21

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