整合多组学分析发现人类肾癌中存在缺陷性 CoQ10 相互作用组

Defective energy metabolism has been established as a hallmark of cancer; however, the specific genetic basis underlying this relationship across cancers remains unclear. Ubiquinone (CoQ10) plays an essential role in regulating efficient generation of mitochondrial ATP and reactive oxygen species levels. Multi-omics assessment of the CoQ10 biosynthesis pathway genes in The Cancer Genome Atlas Program (TCGA) revealed Kidney Clear Cell Carcinoma (KIRC) and Kidney Papillary renal cell carcinoma (KIRP) as cancers that demonstrated a significant relationship between poor prognosis and low expression or copy number deletions in the CoQ10 biosynthesis genes. However, the link between deletions and low expression in CoQ10 biosynthesis genes and poor outcomes remains unknown. Towards this aim, we defined the CoQ10 interactome as a set of 37 protein encoding genes that bind with CoQ10, along with enzymes involved in downstream pathways impacted by CoQ10 homeostasis, based on literature review. We then investigated this CoQ10 interactome for their association with outcomes for KIRC and KIRP patients in TCGA datasets. First, patients were grouped into low/high expression groups based on median gene expression levels for the indication. We then investigated the association of outcome measures Overall Survival (OS) and Progression Free Interval (PFI) with expression groups in KIRC (n=530) and KIRP (n=288) patients. Our results found that low gene expression in 21 of 37 CoQ10 interactome genes in KIRC, and 3 of 37 CoQ10 interactome genes in KIRP were associated with significantly worse OS and PFI. Next, we analyzed copy number deletions and their association with patient outcomes. Patients were grouped as having a deletion in the gene or not. In line with the prior analysis, we observed that deletions in 9 of 37 CoQ10 interactome genes, and 12 of 37 CoQ10 interactome genes were associated with significantly worse OS and PFI in KIRC and KIPR, respectively. Notably, we observed that deletions in ETHDH (KIRC OS HR = 1.95, q-value = 0.0045, n deletion = 75; KIRP OS HR = 5.42, q-value = 0.00008, n deletion = 28) and PRODH (KIRC OS HR = 2.06, q-value = 0.0144, n deletion = 41; KIRP OS HR = 2.71, q-value = 0.01866, n deletion = 60) were associated with significantly poorer OS and PFI in both KIRC and KIRP. These results demonstrate that CoQ10 and its interactome are significantly impacted in kidney cancer subtypes and deletions or low expression in these key genes are associated with poorer survival outcomes for patients. This data indicates potential for therapeutic intervention with BPM31510, a nanoparticle formulation of oxidized CoQ10, which is currently in Phase 2 clinical trials for oncology indications.