Abstract 96P
Background
Colorectal cancer (CRC), is second leading causes of cancer-related deaths. Hence there is an imperative need for the identification of new therapeutic targets. This study aimed to identify genetic variants using genome-wide DNA and RNA sequencing and Pan-Cancer Studies followed by validation cohort & functional analyses.
Methods
RNAseq/DNAseq were used in 146 patients. Gene Ontology, Reactom, Human Disease Ontology were employed. Survival analysis was conducted. The candidate genes were subjected to machine learning-based analysis and ROC. The expression was evaluated by RT-PCR in110 cases. Gene variants were further validated followed by Whole Exome Sequencing in 15 patients. We performed functional analyses in CRC cells via knock down by PIKOI vector for Urocanate Hydratase 1 (UROC1) in cells (CT26-SW480) and then performed Proliferation, 3D Spheroid Model, Cell cycle perturbation, RT-PCR/ELISA and LC-MS/MS.
Results
A total of 2985 DEGs in the advanced stages were identified. Histidine pathway and UROC1 gene were identified as potential prognostic marker. The UROC1 was sensitive, with an AUC of 0.934. The expression levels of the gene were higher in patients. Moreover, our data identified a novel genetic variant in UROC1. ROC curve analysis indicated that UROC1 possesses 70% diagnostic potential, which its value was enhanced by KRAS/NRAS/APC. Functional enrichment analysis underscores the involvement of UROC1 in tumor progression. The prognostic assessment indicates that elevated UROC1 expression correlates with adverse outcomes across multiple GI. Genetic alteration analysis highlights the prevalence of mutations, particularly missense mutations, in UROC1. Significant correlations between UROC1 expression and immune cell infiltration and histidine pathway are observed, suggesting its involvement in tumor immune evasion mechanisms, while its modulation reduces cell growth in CRC cells.
Conclusions
Our study is a world-first, to explore how cancer cells manipulate CRC progression via histidine alterations. Our data illustrated the potential value of UROC1, novel identified variant, rs751617501 in advanced-CRC patients.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.