Dataset Information

Immunosignatures associated with TP53 status and co-mutations classify prognostically head and neck cancer patients.

ABSTRACT:

Background

Immune checkpoint inhibitors (ICIs) are a therapeutic strategy for various cancers although only a subset of patients respond to the therapy. Identifying patients more prone to respond to ICIs may increase the therapeutic benefit and allow studying new approaches for resistant patients.

Methods

We analyzed the TCGA cohort of HNSCC patients in relation to their activation of 26 immune gene expression signatures, as well as their cell type composition, in order to define signaling pathways associated with resistance to ICIs. Results were validated on two cohorts of 102 HNSCC patients and 139 HNSCC patients under treatment with PD-L1 inhibitors, respectively, and a cohort of 108 HNSCC HPV negative patients and by in vitro experiments in HNSCC cell lines.

Results

We observed a significant association between the gene set and TP53 gene status and OS and PFS of HNSCC patients. Surprisingly, the presence of a TP53 mutation together with another co-driver mutation was associated with significantly higher levels of the immune gene expression, in comparison to tumors in which the TP53 gene was mutated alone. In addition, the higher level of TP53 mutated-dependent MYC signature was associated with lower levels of the immune gene expression signature. In vitro and three different patient cohorts validation analyses corroborated these findings.

Conclusions

Immune gene signature sets associated with TP53 status and co-mutations classify with more accuracy HNSCC patients. These biomarkers may be easily implemented in clinical setting.

SUBMITTER: Sacconi A

PROVIDER: S-EPMC10687972 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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Publications

Immunosignatures associated with TP53 status and co-mutations classify prognostically head and neck cancer patients.

Sacconi Andrea A Muti Paola P Pulito Claudio C Urbani Giulia G Allegretti Matteo M Pellini Raul R Mehterov Nikolay N Ben-David Uri U Strano Sabrina S Bossi Paolo P Blandino Giovanni G

Molecular cancer 20231130 1

<h4>Background</h4>Immune checkpoint inhibitors (ICIs) are a therapeutic strategy for various cancers although only a subset of patients respond to the therapy. Identifying patients more prone to respond to ICIs may increase the therapeutic benefit and allow studying new approaches for resistant patients.<h4>Methods</h4>We analyzed the TCGA cohort of HNSCC patients in relation to their activation of 26 immune gene expression signatures, as well as their cell type composition, in order to define ...[more]

PMID: 38031025

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Project description:Integration of high-dimensional tumor gene expression data with clinicopathological data can increase our understanding of disease diversity, enable retrospective patient stratification, and identify new potential biomarkers and therapeutic targets. Using a systems biology approach, we provide a holistic overview of gene co-expression networks in head and neck squamous cell carcinomas (HNSCC). Weighted gene co-expression network analysis of HNSCC RNA sequencing data from 519 patients from The Cancer Genome Atlas (TCGA) was used to determine correlates of 5-year survival, using regression tree-based optimal threshold calculations. Survival-associated gene sets were transformed to gene set scores that were assessed for correlation with clinicopathological data. We identified 8 gene co-expression modules for HNSCC tumors, each of which contained co-expressed genes associated significantly with 5-year survival. Survival-associated co-expression gene signatures correlated dominantly with tumor HPV and p16 status. Network analysis identified that survival was associated with signaling networks of infection, immunity, epithelial-mesenchymal transition (EMT), hypoxia, glycolysis, focal adhesion, extracellular matrix, MYC signaling, autophagy and transcriptional regulation. EMT-associated gene signatures were expressed dominantly in fibroblasts, and cancer-associated fibroblasts were inversely correlated with immune activity. Interestingly, a high Immune Suppression Score based on expression of 21 genes associated with immune inhibition and including immune checkpoints, cytokines and regulatory T cell factors, was also associated with increased survival probability, and was significantly higher in HPV+ HNSCC. Networks associated with HNSCC survival were further associated with survival in cervical cancer, melanoma and lung cancer. This study defines 5129 genes associated with HNSCC survival, organized into co-expressed networks, their correlation with clinicopathological data, and with gene expression data from other malignant diseases, and provides a source for the discovery of biomarkers and novel therapies for HNSCC.

Dataset Information

Immunosignatures associated with TP53 status and co-mutations classify prognostically head and neck cancer patients.

Background

Methods

Results

Conclusions

Publications

Immunosignatures associated with TP53 status and co-mutations classify prognostically head and neck cancer patients.

Similar Datasets

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