Abstract 4177: Integrated assessment of alterations in coenzyme Q biosynthesis genes impacting cancer metabolism leading to critical vulnerabilities in tumors

Abstract Coenzyme Q10 (CoQ) is critical in governing mitochondrial bioenergetics as a pivot point regulating the efficiency of the electron gradient, while balancing electron slippage leading to reactive oxygen species (ROS) generation. Alterations in cancer metabolism are a hallmark of oncogenesis and central is the Warburg Effect, which reflects a dependence on glycolysis due to inefficient mitochondrial function in the presence of oxygen. Alterations in CoQ biosynthesis can disrupt cellular respiration and energy homeostasis, leading to various metabolic disorders. In cancer, restoring proper CoQ function, by correcting its biosynthetic pathway and the levels of CoQ, could offer therapeutic benefits. Targeting CoQ alterations may enhance mitochondrial function and potentially inhibit the proliferation of cancer cells, presenting a novel avenue for cancer treatment. To understand the extent of CoQ biosynthesis imbalance in cancer, gene expression and mutation data for 33 cancers in the TCGA were analyzed. RNA-seq gene expression and SNP mutation data were evaluated for 13 genes in the CoQ biosynthesis pathway: COQ10A, COQ10B, COQ2, COQ3, COQ4, COQ5, COQ6, COQ7, COQ8A, COQ8B, COQ9, PDSS1, and PDSS2. The median expression level of transcripts was examined and 4 genes critical in the biosynthesis pathway demonstrated low median expression across cancers: PDSS1, PDSS2, COQ2, and COQ3. SNP mutations were aggregated across cancers and normalized to gene length for each of the 13 genes. Mutations were low across the 13 genes, with an average of 0.875 SNP mutations observed per 1000 base pairs. Additionally, COQ8A and COQ8B had no observed mutations in any TCGA samples. Kaplan-Meier analysis was performed for each cancer based on low expression (below 25th percentile) and high expression (above 75th percentile) for each CoQ gene. Low Grade Glioma was observed having 6 of 13 genes (COQ10B, COQ2, COQ8A, COQ8B, COQ9, PDSS1) with a significant change in overall survival based on expression levels (logrank test p-value < 0.001). Additionally, 3 genes (COQ5, COQ7, PDSS2) were identified with a significant difference in Kidney Renal Clear Cell Carcinoma, 2 genes each in Adrenocortical Carcinoma (COQ8A, PDSS1), Papillary Renal cell Carcinoma (COQ4, COQ9), and Uveal Melanoma (COQ2, COQ6). In conclusion, this comprehensive analysis of CoQ biosynthesis genes across multiple cancer types reveals critical insights into their expression and mutation profiles, as well as their potential impact on patient survival. The low mutational rates across the 13 genes underscore their importance in maintaining cellular energy homeostasis. Furthermore, the significant survival differences associated with the expression levels of these genes in specific cancers highlight the potential of restoration of CoQ pool as a therapeutic strategy for mitigating dysfunctional energy metabolism. Citation Format: Nischal Mahaveer Chand, Eric M. Grund, Poornima K. Tekumalla, Gregory M. Miller, Niven R. Narain, Vijay Modur, Michael A. Kiebish. Integrated assessment of alterations in coenzyme Q biosynthesis genes impacting cancer metabolism leading to critical vulnerabilities in tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4177.