Effect of KRAS, TP۵۳, SMAD۴, CDKN۲A as diagnostic biomarkers for PDAC cancer

Pancreatic cancer (PaC) is the seventh leading cause of cancer-related deaths. the ۵ year survival rate for PaC is less than ۸%. The primary reason for the poor survival of patients is the late diagnosis and dismal prognosis.Typically, PDAC harbors mutations in key genes such as KRAS, TP۵۳, SMAD۴, and CDKN۲A.The KRAS gene is one of the most common oncogenic alterations and the most frequent gene mutated in PDAC. Unlike the other mentioned genes, it is hyperactivated by point mutations (usually G۱۲D and G۱۲V) on codon ۱۲ of the RAS protein, which is responsible for the constant activation of the P۲۱RAS protein.Mutations in the TP۵۳ gene are detectable in ۶۰-۷۰% of cases. Located on chromosome ۱۷, this gene encodes the p۵۳ protein, also known as the "guardian of the genome." It plays a crucial role in maintaining cellular health by regulating the cell cycle, repairing DNA, and inducing apoptosis.The risk of developing PDAC increases in individuals with pathogenic germline variants of the CDKN۲A gene. This gene encodes the p۱۶INK۴a and p۱۴ARF proteins. Mutations, particularly methylation, play a significant role in PDAC. High methylation levels in blood, pancreatic tissue, and pancreatic fluid samples suggest it as a potential tool for diagnosis and prognosis. typically mutates in the MH۱ and MH۲ codons and is frequently inactivated in PDAC. It plays a vital role in the TGF-β signaling pathway and various biological processes. Loss or mutation of this gene greatly contributes to cancer progression. Methods: We collected relevant articles from December ۹, ۲۰۱۳, to May ۱۴, ۲۰۲۴, using keywords such as KRAS, TP۵۳, SMAD۴, CDKN۲A, Biomarkers, and PDAC in databases such as PubMed, Google Scholar, and ScienceDirect. Our review includes ۱۵ eligible studies. Results: PDAC is one of the most lethal types of cancer worldwide. According to reviews, the likelihood of gene mutations is as follows: KRAS (۸۸%), TP۵۳ (۷۷%), CDKN۲A (۱۸%), SMAD۴ (۲۹%). The KRAS gene is considered an oncogene in pancreatic cancer (PDAC), while TP۵۳, SMAD۴, and CDKN۲A are classified as tumor suppressors. Conclusion: The biomarkers KRAS, TP۵۳, SMAD۴, and CDKN۲A are the most significant molecular events in PDAC. According to conducted studies and research, mutations in the KRAS gene are one of the earliest genetic events in PaC. The persistent activation of this gene leads to the activation of multiple signaling pathways, such as the MARK/ERK (cell proliferation) and AKT/P۱۳K (survival and prevention of apoptosis) pathways. Additionally, mutations in the TP۵۳ gene result in the production of defective proteins that are unable to perform tumor-suppressing functions, leading to treatment resistance, genomic instability, and increased survival of cancer cells. The p۱۶INK۴a protein, produced by CDKN۲A, plays an inhibitory role on the activity of cyclin-dependent kinases (CDK۴/۶). The deletion or inactivation of SMAD۴ directly affects the TGF-β signaling pathway, which promotes invasiveness and metastasis. Like the CDKN۲A gene and other mentioned genes, it leads to the loss of cell cycle control and increased growth of cancer cells. These biomarkers can play a significant role in the diagnosis and prognosis of PDAC.

کلیدواژه ها:

KRAS ، TP۵۳ ، CDKN۲A ، SMAD۴ ، PDAC