Comprehensive Characterization of Transforming Growth Factor Beta Receptor 1 in Stomach Adenocarcinoma Identifies a Prognostic Signature for Predicting Clinical Outcomes and Immune Infiltrates

Abstract

Background: Stomach adenocarcinoma (STAD) is the common cancer and ranks third leading cause of cancer death worldwide. TGF‑β receptor 1 (TGFBR1), serving important roles in the TGF‑β family, the mechanisms whereby TGFβ2 governs tumor progression, immune cell infiltration and its correlation with tumor microenvironment (TME) in STAD remains unintelligible. Methods: First, we used the data in the TCGA, GEPIA, and HPA databases to explore the expression level of TGFBR1 in STAD, the correlation between TGFBR1 expression and the clinical features of STAD, its impact on the survival of STAD. Subsequently, a receiver operating characteristic (ROC) curve and nomogram were constructed and LASSO (the Least Absolute Shrinkage and Selection Operator)-selected features were used to build the TGFBR1 prognostic signature. Moreover, GSEA enrichment analysis is used to find the potential molecular mechanism of TGFBR1 to promote the malignant process of STAD. Finally, we further explored the influence of theTGFBR1 expression on the immune microenvironment of STAD patients through the TIMER2.0 and GEPIA database.Results: In our study, TGFBR1 expression was significantly elevated in patients with STAD and positively co-expression with pathologic stage, lymph node metastases (LNM) stage and histopathological grade of STAD. LASSO-selected features were used to build the TGFBR1 prognostic signature. 9 factors with non-zero coefficients were identified. The corresponding risk scores were computed, according to the following formula: Risk score = (-0.2914) *DIXDC1+ (0.1113) *STON1-GTF2A1L+(0.3092) *FERMT2+(-0.0146) *BHMT2+(0.1798) *ABCC9+(0.068) *MSRB3+(-0.1007) *SYNC+(-0.0891) *SORBS1+(0.0828) *TGFBR1.Survival analysis revealed that patients with high TGFBR1 had shorter OS, FP, and PPS. Multivariate Cox analysis revealed TGFBR1 was an independent prognostic factor for OS in STAD. The receiver operating characteristic (ROC) analysis suggested high diagnostic value with the area under curve (AUC) of TGFBR1 was 0.739, and a prognostic nomogram involving age, T, N, M classification, pathologic stage, primary therapy outcome, histologic grade and TGFBR1 to predict the 1, 3, 5-year OS was constructed. GSEA revealed that high TGFBR1 expression was correlated with pathway in cancer, MAPK signaling pathway, NOTCH signaling pathway, focal adhesion and VEGF-C production. ssGSEA showed that TGFBR1 is correlated with NK cells, Tem and Th17 cells. Furthermore, elevated TGFBR1 expression was found to be significantly correlated with several immune checkpoint and immune markers associated with immune cell subsets. Conclusion: In summary, TGFBR1 could be a prognostic biomarker and an important regulator of immune cell infiltration in STAD. The present study revealed the probable underlying molecular mechanisms of TGFBR1 in STAD and provided a potential target for improving the prognosis.