Burkart Sebastian, Weusthof Christopher, Khorani Karam, Steen Sonja, Stögbauer Fabian, Unger Kristian, Hess Julia, Zitzelsberger Horst, Belka Claus, Kurth Ina, Hess Jochen
Section Experimental and Translational Head and Neck Oncology, Department of Otolaryngology, Head and Neck Surgery, University Hospital Heidelberg, 69120 Heidelberg, Germany.
Department of Oral and Maxillofacial Surgery, University Hospital Heidelberg, 69120 Heidelberg, Germany.
Cancers (Basel). 2023 Mar 8;15(6):1655. doi: 10.3390/cancers15061655.
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).
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.
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).
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.
识别分子定义的癌症亚组并靶向肿瘤特异性弱点，对于改善治疗反应和患者预后具有巨大潜力，但仍是一项具有高度临床相关性且尚未解决的挑战，尤其是在头颈部鳞状细胞癌（HNSC）中。
我们通过多组学数据的综合分析，建立了一个与泛素羧基末端水解酶L1（UCHL1）相关的基因集，以识别和分子表征TCGA-HNSC内的UCHL1相关亚组。基于MSigDB基因集的GSVA分数，在TCGA-HNSC上训练了一个极端梯度提升模型，以稳健预测其他实体瘤及其衍生的癌细胞系中的UCHL1相关癌症。通过计算机药物筛选方法阐明UCHL1相关癌细胞的潜在弱点。
我们建立了一个包含497个基因的基因集，该基因集将TCGA-HNSC队列分层为具有UCHL1相关或其他表型的不同亚组。UCHL1相关的HNSC具有更高频率的基因组改变特征，这在分类模型预测的其他实体瘤的UCHL1相关癌症中也很明显。这些数据表明基因组完整性维持受损以及对DNA损伤治疗的敏感性，这得到了放疗后UCHL1相关肿瘤良好预后以及UCHL1相关癌细胞对辐射或DNA损伤化合物（如奥沙利铂）更高敏感性的支持。
我们的研究将UCHL1相关癌症确立为大多数实体瘤中的一个新亚组，具有独特的分子表型，且DNA损伤治疗是其特定弱点，这需要在临床前模型和未来临床试验中进一步进行概念验证。
