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Characterizing the prognostic and therapeutic value of necroptosis in sarcoma based on necroptosis subtypes
Yibo Ma1, Qihang Yuan2, Shiping He3
1Graduate School of Dalian Medical University, Dalian Medical University, Dalian, China.
Abstract:
Necroptosis, a type of necrotic cell death independent of caspase regulation, is mainly mediated by receptor interacting serine/threonine kinase 1 (RIPK1), receptor interacting serine/threonine kinase 3 (RIPK3) and mixed lineage kinase domain-like (MLKL). Necroptosis plays an essential role in many tumors. However, the potential roles of necroptosis in tumor microenvironment (TME) of sarcoma (SARC) remain unknown. This study analyzed the expression, prognosis, genetic alterations of necroptosis genes in SARC. We identified two subtypes (cluster A and B) by performing unsupervised consensus clustering. Cluster A and B greatly differed in prognosis and immune infiltration, with cluster A showing more favorable prognosis, higher immune infiltration and higher expression levels of necroptosis genes than cluster B. Based on the differentially expressed genes (DEGs) between two clusters, a necroptosis scoring system was developed for predicting overall survival of SARC patients. Patients with high necroptosis score had worse survival status, with a decreased infiltration level of most immune cells. Our findings demonstrated the potential role of necroptosis in regulating tumor microenvironment and the prognostic value of necroptosis-related genes for SARC patients.
Insights
Necroptosis, a regulated cell death pathway, influences sarcoma. This study reveals two distinct sarcoma subtypes based on necroptosis gene expression, impacting prognosis and immune cell infiltration, and develops a scoring system for patient survival prediction.
Area of Science:
- Oncology
- Cell Death Research
- Immunology
Background:
- Necroptosis, a programmed necrosis pathway, is regulated by RIPK1, RIPK3, and MLKL.
- Necroptosis is implicated in various cancers, but its role in sarcoma and its tumor microenvironment (TME) is not well understood.
Purpose of the Study:
- To investigate the expression, prognostic significance, and genetic alterations of necroptosis-related genes in sarcoma (SARC).
- To explore the association between necroptosis pathways and the TME in SARC.
- To develop a predictive model for SARC patient survival based on necroptosis gene expression.
Main Methods:
- Unsupervised consensus clustering was used to classify SARC samples based on necroptosis gene expression.
- Differential gene expression analysis was performed between identified clusters.
- A necroptosis scoring system was constructed using differentially expressed genes (DEGs).
- Prognostic value and immune infiltration levels were analyzed in relation to necroptosis subtypes and scores.
Main Results:
- Two distinct SARC subtypes (cluster A and B) were identified, differing significantly in prognosis and immune infiltration.
- Cluster A exhibited a more favorable prognosis, higher immune infiltration, and increased necroptosis gene expression compared to cluster B.
- A necroptosis scoring system was developed, where a high score correlated with worse overall survival and reduced immune cell infiltration in SARC patients.
Conclusions:
- Necroptosis-related genes play a significant role in shaping the sarcoma TME.
- The identified necroptosis subtypes and the developed scoring system hold prognostic value for SARC patients.
- Targeting necroptosis pathways may offer therapeutic strategies for sarcoma.
