DNA Methylation of PI3K/AKT Pathway-Related Genes Predicts Outcome in Patients with Pancreatic Cancer: A Comprehensive Bioinformatics-Based Study

Abstract

Pancreatic cancer (PCA) is one of the most lethal malignancies worldwide with a 5-year survival rate of 9%. Despite the advances in the field, the need for an earlier detection and effective therapies is paramount. PCA high heterogeneity suggests that epigenetic alterations play a key role in tumour development. However, only few epigenetic biomarkers or therapeutic targets have been identified so far. Here we explored the potential of distinct DNA methylation signatures as biomarkers for early detection and prognosis of PCA. PI3K/AKT-related genes differentially expressed in PCA were identified using the Pancreatic Expression Database (n = 153). Methylation data from PCA patients was obtained from The Cancer Genome Atlas (n = 183), crossed with clinical data to evaluate the biomarker potential of the epigenetic signatures identified and validated in independent cohorts. The majority of selected genes presented higher expression and hypomethylation in tumour tissue. The methylation signatures of specific genes in the PI3K/AKT pathway could distinguish normal from malignant tissue at initial disease stages with AUC > 0.8, revealing their potential as PCA diagnostic tools. ITGA4, SFN, ITGA2, and PIK3R1 methylation levels could be independent prognostic indicators of patients’ survival. Methylation status of SFN and PIK3R1 were also associated with disease recurrence. Our study reveals that the methylation levels of PIK3/AKT genes involved in PCA could be used to diagnose and predict patients’ clinical outcome with high sensitivity and specificity. These results provide new evidence of the potential of epigenetic alterations as biomarkers for disease screening and management and highlight possible therapeutic targets.

Clinical applications of DNA methylation profiling in lung cancer

“…For instance, the subgroup with the best clinical outcome (subgroup number 1), was characterized by the highest DNAm age and no tumor recurrence or reported death whatsoever. This phenotype seemed to be associated with the repression of the PI3K-AKT signaling pathway through hypermethylation, which is in line with previous studies in silico (22). Nevertheless, it would be very interesting to confirm whether this repression significantly reduces protein levels and whether that could be somehow related to the increase in DNAm age observed in this subgroup.…”

Combining single-cell and bulk RNA sequencing, NK cell marker genes reveal a prognostic and immune status in pancreatic ductal adenocarcinoma

“…Moreover, the dysregulation of the cell cycle is also one of the important causes of tumor cell progression. Study of Faleiro et al demonstrated that the methylation of specific genes of PI3K-Akt signaling pathway is responsible for the recurrence and prognosis of pancreatic cancer 41 . All of these indicate a significant relationship between NKCMGS and the occurrence and development of PDAC.…”

PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer

“…Accumulating evidence suggests that epigenetic alterations are as crucial as genetic mutations in dysregulating PAM signaling pathway in different types of cancer [181][182][183][184]. In particular, DNA methylation [185], histone post-translational modifications [186], and non-coding RNAs modulation [187,188], are three main epigenetic mechanisms that affect PAM pathway and have been associated with cancer.…”