Dados do Trabalho

Título

CO-EXPRESSED GENES REVEAL MOLECULAR DISPARITIES IN GASTRIC ADENOCARCINOMA AND AFFECT 5-YEAR OVERALL SURVIVAL (OS) IN LAUREN SUBTYPES

Introdução

Gastric Adenocarcinoma (GAC) is a significant global health concern, with varying incidence and mortality rates across regions. Its complex nature is marked by genetic heterogeneity, which affects diagnosis and treatment strategies. Lauren's classification further highlights this diversity, categorizing tumors into intestinal and diffuse subtypes, but with different genetic profiles within the same subtype. Understanding molecular aspects of the GAC and Lauren subtypes is crucial for discovering new therapeutic targets, effective management and better outcomes.

Objetivo

We aim to identify biomarkers in the Lauren subtypes of GAC useful in diagnosis and personalized treatment strategies.

Métodos

The João de Barros Barreto University Hospital Ethics Committee (CAE 47580121.9.0000.5634) granted ethical approval for the study. We extracted total RNA from adjacent (46%, n=35) and GAC (54%, n=41) tissues. Employing next-generation sequencing (NGS), we obtained gene expression data. Weighted Gene Co-Expression Network Analysis (WGCNA) was used to identify co-expression gene modules. Modules correlated with GAC tissue were subjected to Gene Set Enrichment Analysis (GSEA). Genes exhibiting high expression, sensitivity, and specificity were considered potential hub genes. Association between hub gene expressions and Lauren's diffuse (34%, n=14) and intestinal (66%, n=27) subtypes were examined. Also, OS data from 359 GAC patients were downloaded from the KM Plotter database to validate our findings. The Cox proportional hazards model was fitted using the survival 3.5-5. p-values ≤ 0.05 were considered statistically significant. R was utilized for performing all analyses.

Resultados

After identifying co-expression modules, we selected the MEBrown gene group, which exhibited a positive correlation with the tumor (r = 0.59). Pathways linked to extracellular matrix remodeling and collagen biogenesis displayed upregulated MEBrown genes, as indicated by functional enrichment analysis. Chosen hub genes, MCM7 (AUC = 0.81), MCM2 (AUC = 0.78), MCM3 (AUC = 0.79), NOP58 (AUC = 0.77), NOP56 (AUC = 0.81), TOP2A (AUC = 0.79), and BRCA1 (AUC = 0.74), were all upregulated in tumors and discriminate tumors with high sensitivity and specificity. Notably, only high expression of NOP58 (HR 2.5, 95% CI 0.95-6.6), TOP2A (HR 3.6, 95% CI 1.4 - 9.4), and BRCA1(HR 2.9, 95% CI 1.1-7.9) indicated worse prognosis. All 7 genes showed significantly higher expression in the intestinal Lauren subtype, with positive correlations to KRAS, MET, MYC, CCNE1, CDH1, and SMAD4. Moreover, high expression of NOP58, TOP2A, and BRCA1 in the intestinal subtype marked good prognoses, while their low expression in the diffuse subtype signified poorer outcomes.

Conclusões

Our findings highlight the potential roles of NOP58, TOP2A, and BRCA1 as key regulators of processes involved in tumor extracellular matrix remodeling in GAC. These genes are significantly overexpressed in GAC tissues and exhibit strong discriminatory power for tumor classification. Notably, NOP58, TOP2A, and BRCA1 expression demonstrate distinct prognostic implications in OS of patients according to Lauren's subtypes. Nonetheless, further validations in larger cohorts are imperative.

Palavras-chave

Stomach cancer, intestinal subtype, biomarker

Financiador do resumo

Fundação Amazônia de Amparo a Estudos e Pesquisas - FAPESPA and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES