AUTHOR=Yang Jie , Chen Hua , Wang Yongqiang , Chen Jian 

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

JOURNAL=Frontiers in Genetics

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2022.965799

DOI=10.3389/fgene.2022.965799

ISSN=1664-8021

ABSTRACT=<p><bold>Background:</bold> 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.</p><p><bold>Methods:</bold> Necroptosis-related genes (NRGs) were collected from high-quality literature. Using The Cancer Genome Atlas (TCGA) (<ext-link ext-link-type="uri" xlink:href="https://cancergenome.nih.gov" xmlns:xlink="http://www.w3.org/1999/xlink">https://cancergenome.nih.gov</ext-link>) and the Gene Expression Omnibus (GEO) (<ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/geo" xmlns:xlink="http://www.w3.org/1999/xlink">www.ncbi.nlm.nih.gov/geo</ext-link>) 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.</p><p><bold>Results:</bold> 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.</p><p><bold>Conclusion:</bold> 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.</p>