Research Paper Volume 14, Issue 12 pp 5034—5058
Multi-omics analysis reveals the panoramic picture of necroptosis-related regulators in pan-cancer
- 1 Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin 300060, China
- 2 Department of Hepatobiliary Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin 300060, China
- 3 Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Sino-US Center for Lymphoma and Leukemia Research, Tianjin 300060, China
Received: February 14, 2022 Accepted: May 19, 2022 Published: June 21, 2022
https://doi.org/10.18632/aging.204124How to Cite
Copyright: © 2022 Li et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Background: Unlike apoptosis, necroptosis is a tightly regulated form of programmed cell death (PCD) that occurs in a caspase-independent manner and is mainly triggered by receptor-interacting serine/threonine-protein kinases RIPK1 and RIPK3 and the RIPK3 substrate mixed-lineage kinase domain-like protein (MLKL). A growing body of evidence has documented that necroptosis, as a novel therapeutic strategy to overcome apoptosis resistance, has potential pro- or anti-tumoral effects in tumorigenesis, metastasis, and immunosurveillance. However, comprehensive multi-omics studies on regulators of necroptosis from a pan-cancer perspective are lacking.
Methods: In the present study, a pan-cancer multi-omics analysis of necroptosis-related regulators was performed by integrating over 10,000 multi-dimensional cancer genomic data across 33 cancer types from TCGA, 481 small-molecule drug response data from CTRP, and normal tissue data from GTEx. Pan-cancer pathway-level analyses of necroptosis were conducted by gene set variation analysis (GSVA), including differential expression, clinical relevance, immune cell infiltration, and regulation of cancer-related pathways.
Results: Genomic alterations and abnormal epigenetic modifications were associated with dysregulated gene expression levels of necroptosis-related regulators. Changes in the gene expression levels of necroptosis-related regulators significantly influenced cancer progression, intratumoral heterogeneity, alterations in the immunological condition, and regulation of cancer marker-related pathways. These changes, in turn, caused differences in potential drug sensitivity and the prognosis of patients.
Conclusion: Necroptosis-related regulators are expected to become novel biomarkers of prognosis and provide a fresh perspective on cancer diagnosis and treatment.
Abbreviations
TCGA: the Cancer Genome Atlas; CTRP: cancer therapeutics response portal; GSVA: gene set variation analysis; CNV: copy number variation; SNV: single nucleotide variation; RPPA: reverse phase protein array; PAS: pathway activity score; FDR: false discovery rate; logFC: log fold change; HR: hazard ratio.