Abstract 5475: Wnt pathway pharmacogenetics in lung cancer patients treated with platinum regimens

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Background: The Wnt/β-catenin signaling is important in the development and progression of non-small cell lung cancer (NSCLC). Expression of Wnt pathway components was common in resected NSCLC and was associated with poor prognosis. Moreover, Wnt pathway expression in NSCLC cell lines correlated with increased cell growth and resistance to therapy. The host genotype may modulate the effect of individual biological factors on treatment and clinical outcome. Hence, we assessed Wnt pathway pharmacogenetics in patients with advanced NSCLC receiving platinum-based therapy. Method: Peripheral blood mononuclear cells (PBMCs) were collected from 598 inoperable stage III-IV NSCLC patients receiving platinum regimens. Genomic DNA was extracted from PBMCs and stored at -80o C. Illumina's Infinium iSelect HD Custom Genotyping BeadChip (Illumina, San Diego, CA) standard 3 day protocol was used to assess 441 host SNPs in 50 candidate Wnt pathway genes. BeadStudio software was used to autocall genotypes. SNPs with a call rate <95% were excluded from further analysis. Cox's proportional hazards model was used to estimate Hazard Ratios (HRs), with adjustment for age, sex, ethnicity, smoking status, clinical stage, performance status and therapy modality. The most common genotype served as the reference group. To correct for the effect of multiple comparisons, q values (a false discovery rate [FDR] adjusted P-value) were calculated by a method implemented in the R package. SNPs with q<0.10 were then used in the assessments of the combined effects of unfavorable genotypes. Survival tree analysis was performed to assess higher-order gene-gene interactions, Results: Survival correlated with 57 SNPs from 21 genes. After correcting for multiple comparisons, five SNPs remained significant in multivariate analysis, including the AXIN2 SNPs rs11868547 (Hazard Ratio [HR] for variant vs. reference SNP =0.77 [95% CI, 0.66-0.89], p=0.0006) and rs4541111 (HR=0.77 [0.68-0.91], p<0.002), as well as rs12819505 (Wnt-5B, HR=1.58 [1.19-2.09], p<0.002), rs4413407 (CXXC4, HR=1.28 [1.10-1.50], p<0.002), and rs10878232 (WIF-1, HR=1.36 [1.12-1.66], p<0.003). Cumulative analysis of these SNPs showed the joint effects of unfavorable genotypes on patient survival. Survival tree analysis based on four of these SNPs revealed higher order gene-gene interactions and classified patients into two groups of low and high death risk, with median survival time of 17.3 and 11.3 months respectively (log rank p< 5 × 10−8). Conclusions: Wnt pathway SNPs were significantly associated with survival of NSCLC patients treated with platinum-based chemotherapy. This supports published data suggesting that the Wnt pathway plays an important role in affecting clinical outcome for NSCLC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5475. doi:10.1158/1538-7445.AM2011-5475