Abstract 4506: TNFRSF10B polymorphisms and haplotypes predicts survival in non-small cell lung cancer patients

Abstract

Abstract Introduction: Inflammation is regulated through a balance between pro-inflammatory and anti-inflammatory cytokines. Tumor necrosis factor (TNF), a pro-inflammatory cytokine, is a central mediator of inflammation and is involved in both cancer development and progression. The TNF family inhibits tumorigenesis via apoptosis, but deregulation of TNFs promotes tumor cell tissue invasion, migration, and metastasis. Germline variations in TNF-related genes may influence expression levels and thus influence lung cancer prognosis. We tested this hypothesis in a large series of non-small cell lung cancer patients (NSCLC) treated at the Moffitt Cancer Center. Methods: Using the Illumina GoldenGate Assay we genotyped 305 SNPs from 53 different inflammation-related genes in 651 NSCLC patients. Using multivariable Cox proportional hazard regression all SNPs were analyzed by an additive model for overall survival and were ranked by P-value. Correction for multiple comparisons, haplotype, and stratified analyses were also performed. Results: The overall median survival time was 25 months. Fourteen of the inflammation-related SNPs were significantly associated with NSCLC survival and 4 of the fourteen were located in the TNF-receptor superfamily member 10b gene. The linkage disequilibrium map for the 4 loci revealed r^2 values ranging from 0.36 to 0.66. When compared to the C/C genotype, the T-allele genotypes of the top ranked SNP (TNFRSF10B:rs11785599) were associated with a 41% increased risk of death (95% CI 1.16-1.70) after adjusting for age, gender, smoking, histology, stage, and first course treatment. The risk genotypes for the other three statistically significant TNF loci (rs1047275, rs4460370, and rs883429) exhibited a 35% (95% CI 1.11-1.65), 29% (95% CI 1.06-1.57), and 23% (95% CI 1.00-1.53) increased risk of death, respectively. Haplotype analyses of all four loci revealed that the risk haplotype (TCTT) was associated with a 77% increased risk of death (95% CI 1.25-2.52) when compared to the referent wildtype haplotype (CGCC). Stratified analyses demonstrated that the top ranked SNP (rs11785599) remained significantly associated with survival for both: men and women, early (I + II) and late stage patients (III + IV), and adenocarcinoma and squamous cell carcinoma tumors. When the data were analyzed by chemotherapy regimen, the risk genotypes of rs11785599 were consistently associated with an increased risk of death but the only significant finding was among patients treated with platinum agents plus taxanes (HR = 1.81; 95% CI 1.29-2.52). Conclusions: Although the functional significance of this SNP needs to be elucidated, these data suggest a possible role of TNFRSF10B:rs11785599 in the prognosis of NSCLC. If validated, these data have potential translational implications by optimizing patient-specific therapy based on germline genetics. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4506. doi:1538-7445.AM2012-4506