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Lethal-7-related polymorphisms are associated with susceptibility to and prognosis of gastric cancer.

ABSTRACT: BACKGROUND:The lethal-7 (let-7) family members and their targets are involved in the development and progression of tumors. Let-7-related polymorphisms have been reported to be associated with tumorigenesis and prognosis. In gastric cancer, however, the related studies are limited. AIM:To investigate the role of let-7-related microRNA polymorphisms in the tumorigenesis and prognosis of gastric cancer in a Chinese population. METHODS:A total of 898 gastric cancer patients and 992 tumor-free controls were recruited into this study from 2008 to 2013. Gastric cancer patients were followed periodically. Ten single nucleotide polymorphisms (SNPs) in the let-7 gene region or their target mRNAs were genotyped using the MassARRAY system and their associations with the risk for or overall survival of gastric cancer were analyzed. RESULTS:All the ten SNPs were in Hardy-Weinberg equilibrium. The C allele of the rs3811463 polymorphism in the 3'-untranslated region (UTR) of LIN28A was associated with a lower risk of gastric cancer [odds ratio (OR) = 0.74, 95% confidence interval (CI): 0.61-0.88, P = 0.001] after adjustment for age and Helicobacter pylori status. Seven hundred and thirty-five gastric cancer patients who had undergone radical tumorectomy were included in the survival analysis and their 5-year survival rate was 53.9% (95%CI: 50.1%-57.6%). The rs10889677 in the 3'-UTR of IL23R was corresponded to the prognosis of gastric cancer in a dose-response manner, in which the death risk increased by 25% [hazard ratio (HR) = 1.25, 95%CI: 1.04-1.45, P = 0.011] with each increase in the number of C alleles after controlling for other potential clinicopathological parameters. CONCLUSION:The let-7-related polymorphism rs3811463 in LIN28A is associated with the susceptibility to gastric cancer and the let-7-related polymorphism rs10889677 in IL23R is associated with the prognosis of gastric cancer.

SUBMITTER: Jia ZF

PROVIDER: S-EPMC6397727 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Lethal-7-related polymorphisms are associated with susceptibility to and prognosis of gastric cancer.

Jia Zhi-Fang ZF Cao Dong-Hui DH Wu Yan-Hua YH Jin Mei-Shan MS Pan Yu-Chen YC Cao Xue-Yuan XY Jiang Jing J

World journal of gastroenterology 20190201 8

<h4>Background</h4>The lethal-7 (<i>let-7</i>) family members and their targets are involved in the development and progression of tumors. <i>Let-7</i>-related polymorphisms have been reported to be associated with tumorigenesis and prognosis. In gastric cancer, however, the related studies are limited.<h4>Aim</h4>To investigate the role of <i>let-7</i>-related microRNA polymorphisms in the tumorigenesis and prognosis of gastric cancer in a Chinese population.<h4>Methods</h4>A total of 898 gastr ...[more]

PMID: 30833806

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Project description: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.

Project description:Accumulating evidence indicates that mitochondrial DNA alterations contribute to cancer development and progression. In this study, we evaluated the relationship between polymorphisms of mitochondrial NADH dehydrogenase subunit 3 (MTND3) and the risk of gastric cancer (GC). Five single nucleotide polymorphisms (SNPs; rs28358278, rs2853826, rs201397417, rs41467651, and rs28358275) were identified and genotyped in 377 patients with GC patients and 363 controls by direct sequencing. The rs41467651 T allele was significantly associated with GC risk [adjusted odds ratio (OR) = 2.11, 95% confidence interval (CI) = 1.25-3.55, P = 0.005). In stratified analysis, rs28358278, rs2853826, and rs41467651 were associated with subgroups of GC, with the rs28358278 G, rs2853826 T, and rs41467651 T alleles associated with an increased GC risk in females (adjusted OR = 1.70, 95% CI = 1.08-2.69, P = 0.023; adjusted OR = 1.78, 95% CI = 1.11-2.85, P = 0.016; adjusted OR = 2.07, 95% CI = 1.04-4.12, P = 0.038, respectively). The rs441467651 T allele was also related with GC risk in diffuse-type subjects compared to that of controls (adjusted OR = 2.61, 95% CI = 1.43-4.89, P = 0.002). In addition, The rs441467651 T allele was significantly related with increased GC risk regardless of lymph node metastasis (LNM), T classification, and tumor stage compared to that of controls (adjusted OR = 2.00, 95% CI = 1.12-3.55, P = 0.019 in LNM-negative subjects; adjusted OR = 2.10, 95% CI = 1.05-4.22, P = 0.0379 in LNM-positive subjects; adjusted OR = 1.82, 95% CI = 1.02-3.24, P = 0.042 in T1/T2 subjects; adjusted OR = 2.60, 95% CI = 1.29-5.24, P = 0.007 in T3/T4 subjects; adjusted OR = 1.91, 95% CI = 1.09-3.34, P = 0.025 in tumor stage I (A+B)/II (A+B+C) subjects; adjusted OR = 2.36, 95% CI = 1.12-5.13, P = 0.025 in tumor stage III (A+B+C) subjects) compared to that of controls. Our findings suggest that the rs28358278, rs2853826, and rs41467651 polymorphisms of MTND3 increase the susceptibility to GC development.

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Project description:BackgroundGastric cancer (GC) is one of the most common cancers, with a wide range of symptoms and outcomes. Cancer-associated fibroblasts (CAFs) are newly identified in the tumor microenvironment (TME) and associated with GC progression, prognosis, and treatment response. A novel CAF-associated prognostic model is urgently needed to improve treatment strategies.MethodsThe detailed data of GC samples were downloaded from The Cancer Genome Atlas (TCGA), GSE62254, GSE26253, and GSE84437 datasets, then obtained 18 unique CAF-related genes from the research papers. Eight hundred eight individuals with GC were classified as TCGA or GSE84437 using consensus clustering by the selected CAF-related genes. The difference between the two subtypes revealed in this study was utilized to create the "CAF-related signature score" (CAFS-score) prognostic model and validated with the Gene Expression Omnibus (GEO) database.ResultsWe identified two CAF subtypes characterized by high and low CAFS-score in this study. GC patients in the low CAFS-score group had a better OS than those in the high CAFS-score group, and the cancer-related malignant pathways were more active in the high CAFS-score group, compared to the low CAFS-score group. We found that there was more early TNM stage in the low CAFS-score subgroup, while there was more advanced TNM stage in the high CAFS-score subgroup. The expression of TMB was significantly higher in the low CAFS-score subgroup than in the high CAFS-score subgroup. A low CAFS-score was linked to increased microsatellite instability-high (MSI-H), mutation load, and immunological activation. Furthermore, the CAFS-score was linked to the cancer stem cell (CSC) index as well as chemotherapeutic treatment sensitivity. The patients in the high CAFS-score subgroup had significantly higher proportions of monocytes, M2 macrophages, and resting mast cells, while plasma cells and follicular helper T cells were more abundant in the low-risk subgroup. The CAFS-score was also highly correlated with the sensitivity of chemotherapeutic drugs. The low CAFS-score group was more likely to have an immune response and respond to immunotherapy. We developed a nomogram to improve the CAFS-clinical score's usefulness.ConclusionThe CAFS-score may have a significant role in the TME, clinicopathological characteristics, prognosis, CSC, MSI, and drug sensitivity, according to our investigation of CAFs in GC. We also analyzed the value of the CAFS-score in immune response and immunotherapy. This work provides a foundation for improving prognosis and responding to immunotherapy in patients with GC.

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Lethal-7-related polymorphisms are associated with susceptibility to and prognosis of gastric cancer.

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Lethal-7-related polymorphisms are associated with susceptibility to and prognosis of gastric cancer.

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