Unraveling the Genetic and Epigenetic Landscape of Pancreatic Cancer

Pancreatic cancer (PC) with a five-year survival rate of less than ۱۰% is considered one of the most aggressive and lethal malignancies worldwide, predominantly affecting elderly males. This disease also is characterized by high heterogeneity, metabolic reprogramming, and a dense stromal environment, complicating diagnosis, prognosis, and treatment. It is also striking to note that development of PC relies on multiple factors, including aberrant genetics and epigenetic signs as leading factors. Therefore, it offers insights into both the mechanisms driving tumor genesis and potential therapeutic targets. This review focuses on the genetic driving PC progression. Common genetic alterations include mutations in KRAS, TP۵۳, CDKN۲A, and SMAD۴ are discussed, as these mutations disrupt critical cellular processes such as cell signaling, DNA repair, and cell cycle regulation, promoting tumor growth and metastasis. Germ line mutations in BRCA۱/۲, PALB۲, RNF۴۳, and ATM, along with rarer genetic mutations, including changes in GNAS, PIK۳CA, and NTRK۱/۲/۳, are also reviewed. In addition to genetic mutations, common epigenetic modifications including hyper methylation of tumor suppressor genes like CDKN۲A and MLH۱ as well as chromatin structure alterations such as histone deacetylases (HDACs), histone methyltransferases (HMTs), and EZH۲, which contribute to aberrant gene expression and chromatin remodeling, are reviewed for their potential as diagnostic and prognostic biomarkers. Furthermore, non-coding RNAs and lncRNAs that regulate key cancer pathways driving pancreatic cancer progression are the other discussion topics of this review. The interplay between genetic and epigenetic changes is emphasized, showing how these alterations collectively contribute to PC tumor genesis. This review also inspects emerging diagnostic tools including the use of non-invasive biomarkers, and the development of targeted therapies aimed at genetic mutations and epigenetic regulators. Combination therapies targeting both genetic and epigenetic alterations, offer promising avenues for improving patient outcomes. The findings suggest a need for the development of more personalized treatment approaches based on genetic and epigenetic profiling, which may lead to more effective and individualized interventions for patients with pancreatic cancer. This review adds to the growing body of knowledge by providing a comprehensive overview of molecular alterations in pancreatic cancer and their potential clinical applications.

کلیدواژه ها:

Pancreatic cancer ، Genetic alteration ، KRAS ، Epigenetic alteration