PuSH - Publikationsserver des Helmholtz Zentrums München: A novel subgroup of UCHL1-related cancers is associated with genomic instability and sensitivity to DNA-damaging treatment.

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Burkart, S.* ; Weusthof, C.* ; Khorani, K.* ; Steen, S.* ; Stögbauer, F.* ; Unger, K. ; Hess J. ; Zitzelsberger, H. ; Belka, C. ; Kurth, I.* ; Hess, J.*

A novel subgroup of UCHL1-related cancers is associated with genomic instability and sensitivity to DNA-damaging treatment.

Cancers 15:16 (2023)

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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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