Genetic and Epigenetic of Colorectal Cancer (CRC); a review research

Colorectal cancer (CRC) is driven by both genetic mutations and epigenetic alterations. The major genetic alterations are those affecting the APC, KRAS, BRAF, and TP۵۳ genes. APC alterations occur in ~۸۰% of CRCs and result in a disruption of the WNT signaling pathway through the allowance of β-catenin accumulation. This promotes uncontrolled cellular growth. Inherited APC mutations in familial adenomatous polyposis result in numerous polyps that inevitably progress to cancer if left untreated. KRAS mutations, typical for ۴۰% of CRC cases, activate the two main downstream cascades, the MAPK and PI۳K/AKT pathways, leading to tumor proliferation and resistance to therapy. BRAF is most frequently represented by its BRAFV۶۰۰E variant in a smaller percentage of CRC patients and is associated with aggressive tumor behavior, accompanied by poor clinical outcomes. The TP۵۳ gene is mutated in over ۵۰% of CRC cases, which leads to the loss of its crucial DNA repair and cell cycle functions, subsequently resulting in genetic instability. Epigenetic alterations, including DNA methylation and modification of histones, play major roles in CRC as well. DNA hypermethylation silences tumor suppressor genes such as MLH۱ and MGMT. Hypermethylation of MLH۱ is highly associated with the incidence of microsatellite instability, which generally has a good prognosis but is resistant to certain therapies. Global DNA hypomethylation, generally occurring in early CRC, contributes to genomic instability. Other histone modifications, overexpression of HDACs, and finally, abnormal histone methylation in CRC are responsible for the suppression of tumor suppressor genes. ncRNAs, especially miRNAs and lncRNAs, have a further regulatory role in CRC. For example, miR-۲۱ is often upregulated in CRC, and its target tumor suppressor genes are mostly PTEN, hence facilitating tumor growth and chemoresistance. lncRNAs, for example, HOTAIR, promote gene silencing by interacting with chromatin modifiers, hence further driving cancer forward. These genetic and epigenetic changes are not mutually exclusive, but rather interact with one another. The most common accompanying epigenetic change to APC mutations is epigenetic silencing of WNT antagonists that amplifies the oncogenic effect. Other examples include hypermethylation of tumor suppressors such as RASSF۱A in KRAS-mutant CRCs, further driving tumor growth and invasion. These epigenetic therapies, which involve DNA methylation inhibitors such as ۵-azacytidine and HDAC inhibitors including vorinostat, have been successful in reversing gene silencing and reactivating tumor suppressors. Such therapies may be used to improve outcomes by allowing other treatments to overcome resistance. Such an understanding of the complex interaction between these genetic mutations and epigenetic changes is crucial in devising personalized therapies against CRC; thus, it holds much promise for an improved prognosis and more effective treatment strategies. This article is based on research and analysis conducted across several relevant papers published in reputable international journals.

کلیدواژه ها:

Colorectal cancer ، Genetic mutations ، Epigenetic alterations ، DNA methylation