Stewart D J, Chang D W, Ye Y, Spitz M, Lu C, Shu X, Wampfler J A, Marks R S, Garces Y I, Yang P, Wu X
Division of Medical Oncology, University of Ottawa, The Ottawa Hospital, Ottawa, ON, Canada.
Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Pharmacogenomics J. 2014 Dec;14(6):509-22. doi: 10.1038/tpj.2014.21. Epub 2014 Jul 1.
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.
非小细胞肺癌（NSCLC）中无翅型蛋白（Wnt）/β-连环蛋白信号通路改变与预后不良及耐药相关。在MD安德森癌症中心（MDACC）接受铂类化疗的598例Ⅲ-Ⅳ期NSCLC患者中，我们将生存情况与50个Wnt信号通路基因中的441个宿主单核苷酸多态性（SNP）进行关联分析。随后，我们在240例接受铂类化疗的晚期NSCLC梅奥诊所患者、127例接受铂类辅助化疗的MDACC患者以及340例仅接受手术治疗的MDACC早期患者（队列2-4）中评估了最显著的SNP。多因素分析显示，生存情况与AXIN2（rs11868547和rs4541111，其中rs11868547在队列2-4中进行评估）、Wnt-5B（rs12819505）、CXXC4（rs4413407）和WIF-1（rs10878232）的SNP相关。具有1个、2个和3-5个不良基因型的患者中位生存期分别为19.7个月、15.6个月和10.7个月（P=3.8×10⁻⁹）。生存树分析将患者分为两组（中位生存时间分别为11.3个月和17.3个月，P=4.7×10⁻⁸）。在队列2-4中，没有一个SNP达到显著水平；然而，其中3个SNP的趋势与队列1相同。通过在线数据库，我们发现rs10878232与LEMD3的表达显示出表达数量性状位点相关性，LEMD3是一个先前与NSCLC生存相关的邻近基因。总之，队列1的结果为Wnt在NSCLC中的重要作用提供了进一步证据。对晚期NSCLC患者进行Wnt抑制剂研究是合理的。队列2-4中SNP与预后缺乏关联可能是由于统计效能低、患者异质性的影响或队列1中的假阳性观察结果。
