Development and validation of a robust necroptosis related classifier for colon adenocarcinoma

Background: Necroptosis, a novel form of apoptosis, plays a crucial function in the progression of colon adenocarcinoma (COAD) and is expected to be triggered in cancer therapy for enhancing anti-tumor immunity. However, the function of necroptosis in tumors and its relationship with the tumor microenvironment (TME) remains largely unclear.Methods: Necroptosis-related genes (NRGs) were collected from high-quality literature. Using The Cancer Genome Atlas (TCGA) (https://cancergenome.nih.gov) and the Gene Expression Omnibus (GEO) (www.ncbi.nlm.nih.gov/geo) meta-cohorts, a robust risk model was constructed to systematically examine the clinical value, functional status, the role of TME based on the risk model, as also the genomic variations.Results: A risk model containing nine NRGs, including TNF receptor-associated factor (TRAF2), TNF receptor 1 associated via death domain (TRADD), ubiquitin carboxyl-terminal hydrolase 21 (USP21), TNF receptor superfamily, member 6 (FAS), tumor necrosis factor receptor superfamily 10B (TNFRSF10B), mitogen-activated protein kinase 8 (MAPK8), mixed lineage kinase domain-like (MLKL), TNF receptor-associated factor 5 (TRAF5), and recombinant receptor-interacting serine-threonine kinase 3 (RIPK3), was constructed. The risk model’s stability and accuracy were demonstrated in training, as also the validation cohorts; it was verified as an independent prognostic model for COAD. High-risk group patients developed “cold” tumors having active tumor proliferation and immunosuppression, while those in the low-risk group developed “hot” tumors with active immune and cell killing functions. Moreover, a higher number of copy number variations in the genome and fewer somatic mutations were found in high-risk group patients. Furthermore, higher sensitivity towards immunotherapy and chemotherapy was seen in patients of the low-risk group.Conclusion: A reliable risk model based on NRGs to assess patient prognosis and guide clinical decision-making was constructed and validated. Our findings may contribute to the understanding of necroptosis and are expected to aid clinical management and guide precision treatment for patients with COAD.

Abstract licence: CC BY

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