A novel subgroup of UCHL1-related cancers is associated with genomic instability and sensitivity to DNA-damaging treatment
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)...
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| Main Authors: | , , , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
8 March 2023
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| In: |
Cancers
Year: 2023, Volume: 15, Issue: 6, Pages: 1-16 |
| ISSN: | 2072-6694 |
| DOI: | 10.3390/cancers15061655 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.3390/cancers15061655 Verlag, lizenzpflichtig, Volltext: https://www.mdpi.com/2072-6694/15/6/1655 
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| Author Notes: | Sebastian Burkart, Christopher Weusthof, Karam Khorani, Sonja Steen, Fabian Stögbauer, Kristian Unger, Julia Hess, Horst Zitzelsberger, Claus Belka, Ina Kurth and Jochen Hess |
| Summary: | 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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| Item Description: | Gesehen am 24.04.2023 |
| Physical Description: | Online Resource |
| ISSN: | 2072-6694 |
| DOI: | 10.3390/cancers15061655 |