Necroptosis-Associated Molecular Subtype and Prognostic Signature Establishment in Patients with Stomach Adenocarcinoma

Junjie Ni, Pu Wu, Lutong Liu, Miaomiao Jin, Changzhen Lei, Chaoyang Xu, Zhongwu Hong

Article ID: 6883
Vol 36, Issue 3, 2022
DOI: https://doi.org/10.23812/j.biol.regul.homeost.agents.20223603.57
Received: 9 July 2022; Accepted: 9 July 2022; Available online: 9 July 2022; Issue release: 9 July 2022

Abstract

Background: Gastric cancer (GC) is the number five most prevalent malignancy globally and the third deadliest, and GC patients have a poor prognosis. Necroptosis is a kind of regulatory cell death, mainly controlled by MLKL, RIP1, and RIP3. In tumor immunotherapy, necroptosis has been shown to be related to antitumor immune responses. Methods: Molecular subtypes of GC tissue in TCGA database was identified based upon necroptosis-associated mRNAs through a ConsensusClusterPlus analysis. Prognosis and tumor immune microenvironment differences were assessed between subtypes. Based on the molecular subtypes, Cox and LASSO regression analyses were employed to identify a prognostic gene model. Patients with stomach adenocarcinoma (STAD) were separated into different risk groups using the model. An established predictive model was assessed via Kaplan–Meier survival analyses and ROC curve analysis. Function enrichment and immunity analysis were conducted to gain additional relevance regarding the mechanistic roles and clinical relevance of the genes. External validation was performed using a GEO dataset. Results: mRNA expression profiles of necroptosis revealed two molecular subtypes (cluster1, cluster2) with distinct prognostic and tumor immune features. A prognostic signature consisting of 11 genes was constructed to separate patients into high- and low-risk subgroups. The C2 subtype and high-risk subgroup not only exhibited worse prognosis but also had universally significantly increased immune cell infiltration and immune-related pathway activation relative to the C1 subtype and low-risk subgroup. The AUCs for 1-, 3-, and 5-year OS were 0.669, 0.692, and 0.747 in the TCGA cohort and 0.548, 0.588, and 0.600 in the GEO cohort. Age, T and N stage, and riskScore were all independent predictors of patient outcomes in both cohorts. Functional analyses revealed that differentially expressed genes (DEGs) between these two risk subgroups were mostly involved in metastasis-related pathways. Conclusions: This study identified two necroptosis-related molecular subtypes exhibiting distinct prognoses and tumor immunological characteristics. Moreover, a 11-gene risk signature was identified, with which patients were separated into low- and high-risk subgroups, which could help clinicians make decisions and personalize treatment.


Keywords

stomach adenocarcinoma;necroptosis;prognosis;tumor microenvironment


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