title: Wnt signaling pathway pharmacogenetics in non-small cell lung cancer.
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.
authors: Division of Medical Oncology, University of Ottawa, The Ottawa Hospital, Ottawa, ON, Canada.
authors: D J
authors: DJ
authors: Stewart
authors: Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: D W
authors: DW
authors: Chang
authors: Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Y
authors: Y
authors: Ye
authors: Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: M
authors: M
authors: Spitz
authors: Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: C
authors: C
authors: Lu
authors: Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: X
authors: X
authors: Shu
authors: Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors: J A
authors: JA
authors: Wampfler
authors: Department of Medical Oncology, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors: R S
authors: RS
authors: Marks
authors: Department of Radiation Oncology, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors: Y I
authors: YI
authors: Garces
authors: Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors: P
authors: P
authors: Yang
authors: Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: X
authors: X
authors: Wu
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D015331:Cohort Studies; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D051153:Wnt Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000187:drug effects / Q000235:genetics*
chemical_list: D051153:Wnt Proteins