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Genes 2018, 9(12), 631; https://doi.org/10.3390/genes9120631

Association between Polymorphisms in Inflammatory Response-Related Genes and the Susceptibility, Progression and Prognosis of the Diffuse Histological Subtype of Gastric Cancer

1
Centro de Investigacao Translacional em Oncologia (LIM24), Departamento de Radiologia e Oncologia, Instituto do Cancer do Estado de Sao Paulo (ICESP), Faculdade de Medicina da Universidade de Sao Paulo (FMUSP), Sao Paulo 01246-000, Brazil
2
Departamento de Gastroenterologia, Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo (HC-FMUSP), Sao Paulo 01246-000, Brazil
3
Departamento de Gastroenterologia, Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo (HC-FMUSP); Instituto do Cancer do Estado de Sao Paulo (ICESP), Sao Paulo 01246-000, Brazil
4
Laboratorio de Epidemiologia e Imunobiologia (LIM38), Departamento de Medicina Preventiva, Faculdade de Medicina da Universidade de Sao Paulo (FMUSP), Sao Paulo 01246-000, Brazil
5
Departamento de Patologia (LIM14), Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo (HC-FMUSP), Sao Paulo 01246-000, Brazil
6
CICAP, Anatomia Patologica, Hospital Alemao Oswaldo Cruz, Sao Paulo 01327-001, Brazil
*
Author to whom correspondence should be addressed.
This paper is dedicated to the memory of Dr Carlos E Jacob, who recently passed away.
Received: 31 October 2018 / Revised: 3 December 2018 / Accepted: 3 December 2018 / Published: 13 December 2018
(This article belongs to the Special Issue Genetic Epidemiology of Complex Diseases in Latin America)
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PDF [360 KB, uploaded 17 December 2018]

Abstract

The chronic inflammatory microenvironment and immune cell dysfunction have been described as critical components for gastric tumor initiation and progression. The diffuse subtype is related to poor clinical outcomes, pronounced inflammation, and the worst prognosis. We investigated the association of polymorphisms in inflammatory response-related genes (COX-2, OGG1, TNFB, TNFA, HSPA1L, HSPA1B, VEGFA, IL17F, LGALS3, PHB, and TP53) with gastric cancer susceptibility, progression and prognosis in a Brazilian sample, focusing on the diffuse subtype. We also performed the analysis regarding the total sample of cases (not stratified for tumor subtypes), allowing the comparison between the findings. We further investigated the polymorphisms in linkage disequilibrium and performed haplotype association analyses. In the case-control study, rs1042522 (TP53) was associated with a stronger risk for developing gastric cancer in the sample stratified for diffuse subtype patients when compared to the risk observed for the total cases; CTC haplotype (rs699947/rs833061/rs2010963 VEGFA) was associated with risk while rs699947 was associated with protection for gastric malignancy in the total sample. Regarding the associations with the clinicopathological features of gastric cancer, for the diffuse subtype we found that rs699947 and rs833061 (VEGFA) were associated with outcomes related to a worse progression while rs5275 (COX-2), rs909253 (TNFB), and rs2227956 (HSPA1L) were associated to a better progression of the disease. In the total sample, rs699947 and rs833061 (VEGFA), rs4644 (LGALS3), and rs1042522 (TP53) were able to predict a worse progression while rs5275 (COX-2), rs2227956 (HSPA1L), and rs3025039 (VEGFA) a better progression. Besides, rs909253 (TNFB) predicted protection for the overall and disease-free survivals for gastric cancer. In conclusion, 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 cancer. View Full-Text
Keywords: gastric cancer; diffuse histological subtype of Lauren; genetic polymorphisms; haplotypes; inflammation; genetic association studies; genetic predisposition to disease; disease progression; prognosis gastric cancer; diffuse histological subtype of Lauren; genetic polymorphisms; haplotypes; inflammation; genetic association studies; genetic predisposition to disease; disease progression; prognosis
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Furuya, T.K.; Jacob, C.E.; Tomitão, M.T.P.; Camacho, L.C.C.; Ramos, M.F.K.P.; Eluf-Neto, J.; Alves, V.A.F.; Zilberstein, B.; Cecconello, I.; Ribeiro, U., Jr.; Chammas, R. Association between Polymorphisms in Inflammatory Response-Related Genes and the Susceptibility, Progression and Prognosis of the Diffuse Histological Subtype of Gastric Cancer. Genes 2018, 9, 631.

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