Abstract A21: Association between polymorphisms in inflammatory response related-genes and the susceptibility, progression, and prognosis of gastric cancer

Abstract

Abstract Introduction: The chronic inflammatory microenvironment in the stomach has been described as a critical component for both tumor initiation and progression. Furthermore, genetic variants have been shown to influence the inter-individual variations in the inflammatory response. Therefore, we aimed to investigate whether polymorphisms in inflammatory response related-genes were associated with risk for gastric tumor development, clinical outcomes, and overall and disease-free survival of this disease in a Brazilian population sample. Methods: Sixteen selected genetic variants in eleven genes (COX-2, OGG1, TNFB, TNFA, HSPA1L, HSPA1B, VEGFA, IL17F, LGALS3, PHB, and TP53) were genotyped in 262 control individuals and 178 gastric cancer patients. Genetic association analyses were investigated in different models (Genotype, Allele, Dominant, and Recessive) in both total sample (N=178) and stratified for the diffuse histologic subtype based on Lauren´s classification (N=112). We also calculated the linkage disequilibrium among the polymorphisms and the haplotype associations were carried out using Haploview and PLINK softwares. Results: Regarding the susceptibility genetic markers, we found that rs1042522 (TP53) Pro allele carriers presented about 2-fold higher risk for developing gastric cancer in a multivariate analysis and this association was even stronger when analyzing only cases with the diffuse subtype. We also found that CTC haplotype (composed by rs699947, rs833061, and rs2010963 of VEGFA) was associated with gastric malignancy. On the other hand, the presence of A allele of rs699947 (VEGFA) was associated with a protection against developing this disease. Regarding the disease progression, the following polymorphisms/haplotypes were able to predict outcomes associated with a worse aggressiveness: rs689466 (COX-2); rs1052133 (OGG1); rs699947, rs833061, and rs2010963 (VEGFA); rs4644 (LGALS3); rs1042522 (TP53); GG haplotype (TNFB/TNFA); ACG and CTC haplotype (VEGFA) and GT haplotype (rs689466 and rs5275 of COX-2 gene). On the other hand, other variants were associated with better outcomes: rs5275 (COX-2); rs2227956 (HSPA1L), and rs3025039 (VEGFA). We also observed that the rs909253 (TNFB) polymorphism was able to predict a better outcome only when stratifying for the individuals diagnosed with the diffuse subtype. Finally, regarding the impact on prognosis, rs909253 (TNFB) was associated with a favorable prognosis when analyzing both the overall and disease-free survivals while rs4644 (LGALS3) His allele carriers presented a worse prognosis with shorter disease-free survival time. Conclusions: These results helped us to clarify the potential role of these polymorphisms in genes involved in the modulation of the inflammatory response in the pathogenesis of gastric malignancy, highlighting that the host genetic variants might act together with other factors to influence the susceptibility, progression, and prognosis of gastric cancer. Citation Format: Tatiane K. Furuya, Carlos E. Jacob, Michele T. Tomitão, Lizeth C. Cordoba-Camacho, Marcus K. Ramos, José Eluf-Neto, Venâncio A. Alves, Bruno Zilberstein, Ivan Cecconello, Ulysses Ribeiro-Junior, Roger Chammas. Association between polymorphisms in inflammatory response related-genes and the susceptibility, progression, and prognosis of gastric cancer [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr A21.