Determination and characterization of molecular heterogeneity and precision medicine strategies of patients with pancreatic cancer and pancreatic neuroendocrine tumor based on oxidative stress and mitochondrial dysfunction-related genes

Abstract

Background: Mitochondria are significant both for cellular energy production and reactive oxygen/nitrogen species formation. However, the significant functions of mitochondrial genes related to oxidative stress (MTGs-OS) in pancreatic cancer (PC) and pancreatic neuroendocrine tumor (PNET) are yet to be investigated integrally. Therefore, in pan-cancer, particularly PC and PNET, a thorough assessment of the MTGs-OS is required.

Methods: Expression patterns, prognostic significance, mutation data, methylation rates, and pathway-regulation interactions were studied to comprehensively elucidate the involvement of MTGs-OS in pan-cancer. Next, we separated the 930 PC and 226 PNET patients into 3 clusters according to MTGs-OS expression and MTGs-OS scores. LASSO regression analysis was utilized to construct a novel prognostic model for PC. qRT-PCR(Quantitative real-time PCR) experiments were performed to verify the expression levels of model genes.

Results: The subtype associated with the poorest prognosis and lowerest MTGs-OS scores was Cluster 3, which could demonstrate the vital function of MTGs-OS for the pathophysiological processes of PC. The three clusters displayed distinct variations in the expression of conventional cancer-associated genes and the infiltration of immune cells. Similar molecular heterogeneity was observed in patients with PNET. PNET patients with S1 and S2 subtypes also showed distinct MTGs-OS scores. Given the important function of MTGs-OS in PC, a novel and robust MTGs-related prognostic signature (MTGs-RPS) was established and identified for predicting clinical outcomes for PC accurately. Patients with PC were separated into the training, internal validation, and external validation datasets at random; the expression profile of MTGs-OS was used to classify patients into high-risk (poor prognosis) or low-risk (good prognosis) categories. The variations in the tumor immune microenvironment may account for the better prognoses observed in high-risk individuals relative to low-risk ones.

Conclusions: Overall, our study for the first time identified and validated eleven MTGs-OS remarkably linked to the progression of PC and PNET, and elaborated the biological function and prognostic value of MTGs-OS. Most importantly, we established a novel protocol for the prognostic evaluation and individualized treatment for patients with PC.

Keywords: mitochondrial dysfunction; molecular heterogeneity; oxidative stress; pancreatic cancer; pancreatic neuroendocrine tumor; precision medicine.