Evaluation of a seven gene mutational profile as a prognostic factor in a population-based study of clear cell renal cell carcinoma

Abstract

In this study, we investigate the influence of the seven genes (VHL, PBRM1, SETD2, BAP1, KDM5C, MTOR and TP53) most frequently mutated in clear cell renal cell cancer (ccRCC) on cancer-specific survival (CSS) in the prospective Netherlands Cohort Study on diet and cancer. DNA isolated from routinely archived formalin-fixed paraffin-embedded tumour blocks from 252 incident ccRCC cases was available for targeted next generation sequencing. Based on the sequencing quality and the completeness of information on clinical characteristics and follow-up, we could use 110 cases for survival analysis. The association with CSS for each mutated gene in these cases was tested using multivariable Cox proportional hazards models to estimate hazards ratios (HR) and confidence intervals (CIs), and we observed mutations in one or more of the seven genes in 64 out of 110 cases (58%). In the multivariable-adjusted analyses, mutations in VHL and PBRM1 were associated with better CSS (HRs (95% CI) 0.34 (0.13‒0.89) and 0.17 (0.04–0.66), respectively), although these results were not statistically significant after multiple testing correction. No association was observed for the other five genes, which may be attributable to limited power.

Molecular subtypes of clear cell renal carcinoma based on PCD-related long non-coding RNAs expression: insights into the underlying mechanisms and therapeutic strategies

“…These include the upregulation of aerobic glycolysis (known as the Warburg effect), the pentose phosphate pathway, fatty acid synthesis, glutamine and glutathione metabolism, along with the downregulation of the tricarboxylic acid (TCA) cycle, fatty acid beta-oxidation (FAO), and oxidative phosphorylation. Studies suggest that the downregulation of the TCA cycle, coupled with the upregulation of the pentose phosphate pathway and fatty acid synthesis, may correlate with the aggressiveness of ccRCC tumors and unfavorable patient prognosis [ 6 , 7 , 10 , 11 ]. Metabolomic analyses reveal a significant increase in glucose uptake and utilization in ccRCC tumor samples, primarily attributed to compromised mitochondrial bioenergetics and oxidative phosphorylation processes, further facilitated by heightened glucose utilization through the pentose phosphate pathway.…”

“…Perturbations in the levels of biochemical enzymes, substrates, metabolites, and end products resulting from metabolic reprogramming serve as valuable diagnostic biomarkers. For instance, overexpression of SETD8 in RCC correlates closely with lipid accumulation, advanced tumor grading and staging, and poor prognosis [ 7 – 10 ]. Furthermore, aberrations in hormone secretion and energy metabolism likely play pivotal roles in the complex process of programmed cell death in tumor cells, intricately linking with tumor initiation, progression, metastasis, and therapeutic response [ 11 ].…”

“…Acting as regulators, lncRNAs exhibit extensive and nuanced effects on the metabolic pathways and products of ccRCC, exerting influence either directly or indirectly. This integrated regulatory role underscores their significance in advancing research on tumor metabolism, facilitating the discovery of novel tumor biomarkers, and pinpointing potential therapeutic targets for future investigations [ 5 , 7 , 10 , 11 ].…”

Renal Cell Carcinoma as a Metabolic Disease: An Update on Main Pathways, Potential Biomarkers, and Therapeutic Targets

“…Furthermore, it has been made clear that epigenetic changes affect the metabolic shift in ccRCC and that, in turn, metabolic intermediates may have an impact on how the genome is expressed during ccRCC progression. A recent study showed that RCC significantly overexpressed SETD8, which was strongly associated with lipid storage, advanced tumor grade and stage, and poor prognosis [24]. Conversely, the increased level of the oncometabolite 2-hydroxyglutarate has been associated with epigenetic modifications which promote a neoplastic phenotype [25].…”