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Open Access Gold möglich sobald Verlagsversion bei der ZB eingereicht worden ist.
A novel subgroup of UCHL1-related cancers is associated with genomic instability and sensitivity to DNA-damaging treatment.
Cancers 15:16 (2023)
PURPOSE: Identification of molecularly-defined cancer subgroups and targeting tumor-specific vulnerabilities have a strong potential to improve treatment response and patient outcomes but remain an unmet challenge of high clinical relevance, especially in head and neck squamous cell carcinoma (HNSC). EXPERIMENTAL DESIGN: We established a UCHL1-related gene set to identify and molecularly characterize a UCHL1-related subgroup within TCGA-HNSC by integrative analysis of multi-omics data. An extreme gradient boosting model was trained on TCGA-HNSC based on GSVA scores for gene sets of the MSigDB to robustly predict UCHL1-related cancers in other solid tumors and cancer cell lines derived thereof. Potential vulnerabilities of UCHL1-related cancer cells were elucidated by an in-silico drug screening approach. RESULTS: We established a 497-gene set, which stratified the TCGA-HNSC cohort into distinct subgroups with a UCHL1-related or other phenotype. UCHL1-related HNSC were characterized by higher frequencies of genomic alterations, which was also evident for UCHL1-related cancers of other solid tumors predicted by the classification model. These data indicated an impaired maintenance of genomic integrity and vulnerability for DNA-damaging treatment, which was supported by a favorable prognosis of UCHL1-related tumors after radiotherapy, and a higher sensitivity of UCHL1-related cancer cells to irradiation or DNA-damaging compounds (e.g., Oxaliplatin). CONCLUSION: Our study established UCHL1-related cancers as a novel subgroup across most solid tumor entities with a unique molecular phenotype and DNA-damaging treatment as a specific vulnerability, which requires further proof-of-concept in pre-clinical models and future clinical trials.
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Publikationstyp
Artikel: Journalartikel
Dokumenttyp
Wissenschaftlicher Artikel
Schlagwörter
Hnscc) ; Head And Neck Squamous Cell Carcinoma (hnsc ; Integrative Multi-omics Analysis ; Pan-cancer ; Radiotherapy ; Ubiquitin C-terminal Hydrolase L1; C-terminal Hydrolase-l1; Ubiquitin; Uchl1; Head
ISSN (print) / ISBN
2072-6694
Zeitschrift
Cancers
Quellenangaben
Band: 15,
Heft: 6,
Artikelnummer: 16
Verlag
MDPI
Verlagsort
St Alban-anlage 66, Ch-4052 Basel, Switzerland
Nichtpatentliteratur
Publikationen
Begutachtungsstatus
Peer reviewed
Institut(e)
Research Unit Radiation Cytogenetics (ZYTO)
CCG Personalized Radiotherapy in Head and Neck Cancer (KKG-KRT)
CCG Personalized Radiotherapy in Head and Neck Cancer (KKG-KRT)