Pan-cancer assessment of deletions in COQ biosynthesis pathway genes associated with poor prognosis and potential benefit from BPM31510 intervention in kidney cancers.

Abstract

500 Background: 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 mitochondrial ATP generation and reactive species levels. Maintenance of CoQ10 levels is orchestrated by 13 CoQ10 biosynthetic genes that, when altered, results in severe metabolic dysfunction. However, the mutational, deletion/amplification, methylation, or mRNA expression status across cancers has not been thoroughly investigated. Methods: Towards this aim, we comprehensively molecularly analyzed 33 cancer types (n = 10535) from The Cancer Genome Atlas Program (TCGA) dataset to identify cancers that demonstrated poor prognosis associated with alterations in the COQ10 biosynthesis pathway. Pan-cancer in-silico analysis of expression, mutations, copy number alteration, and methylation of the COQ10 biosynthesis pathway genes, along with a subset of associated genes, was performed on the data. Across the 33 indications in TCGA, we identified Clear Cell Carcinoma (KIRC) (n = 530) and Papillary renal cell carcinoma (KIRP) (n = 288) as primary cancers that demonstrated a significantly poor prognosis with deletions in COQ10 biosynthesis genes. Results: Deletions in COQ2 (HR 2.35 (1.64 – 3.37); q-val = 0.0003), COQ4 (HR 1.76 (1.29 – 2.38); q-val = 0.009), and COQ6 (1.69 (1.25 – 2.28); q-val = 0.017) were associated with poor survival in KIRC. Deletions in these same genes were also associated with poor survival in KIRP, COQ2 (HR 5.86 (2.97 – 11.58); q-val = 0.00005), COQ4 (HR 3.27 (1.64 – 6.51); q-val = 0.018), and COQ6 (3.49 (1.83 – 6.65); q-val = 0.007). The incidence of one or more deletions was 63% in KIRC and 28% in KIRP cancers. Further, we investigated the association of several key proteins and their respective genes with known interaction with COQ10 for ATP generation in the mitochondrion relative to patient outcome. We observed 3 genes in KIRC and 6 genes in KIRP demonstrated an association with both poor survival and progression, with NDUFS7 (KIRC HR 4.45 q-val < 0.0001; KIRP HR 3.8 q-val = 0.032) and PRODH (KIRC HR 2.06 q-val = 0.029; KIRP HR 2.71 q-val = 0.032) demonstrating significance in both indications. Conclusions: This unbiased pan-cancer analysis clearly demonstrates that kidney cancers (KIRC/KIRP) may predominantly exhibit a genetic basis for altered mitochondrial metabolism due to a loss of ability to produce COQ10, further pushing the cells into glycolysis over aerobic respiration rendering them susceptible to metabolic interventions. Currently, we are developing a nanodispersion formulation of oxidized CoQ10 (BPM31510) that delivers supraphysiological levels of CoQ10 into circulation and into tumors, which is currently being investigated in Phase 2 clinical trials.