Genetic and Molecular Mechanisms in Colorectal Cancer: Pathways to Targeted Therapies

Colorectal cancer (CRC) is a prevalent and life-threatening malignancy of the colon and rectum, ranking among the leading causes of cancer-related deaths globally. The clinical pathway of CRC necessitates a comprehensive understanding of molecular mechanisms, genetic predispositions, and the sequence of changes leading to disease development and progression. Approximately ۱۰% of CRC cases are attributed to inherited genetic mutations, with Lynch syndrome and Familial Adenomatous Polyposis (FAP) being significant contributors. Lynch syndrome involves mutations in DNA mismatch repair (MMR) genes (MLH۱, MSH۲, MSH۶, PMS۲), compromising DNA repair and leading to mutations and cancer. FAP is characterized by mutations in the adenomatous polyposis coli (APC) gene, resulting in numerous polyps in the colon and rectum, thereby increasing cancer risk. Several molecular pathways are pivotal in CRC pathogenesis, including the Wnt/β-catenin signaling pathway, where APC gene mutations stabilize β-catenin, leading to uncontrolled cell division and tumorigenesis. The KRAS signaling pathway, with KRAS mutations activating downstream pathways (MAPK/ERK, PI۳K/AKT), drives cell proliferation and survival. The TGF-β signaling pathway, typically a tumor suppressor, can promote cancer progression when mutated (e.g., SMAD۴). Microsatellite instability (MSI), a genetic hypermutation resulting from impaired MMR, appears in about ۱۵% of CRCs and is typical in Lynch syndrome-associated cancers. MSI-high tumors have a better prognosis and distinct chemotherapy responses compared to microsatellite stable (MSS) tumors. Epigenetic changes, such as DNA methylation and histone modifications, also play significant roles. For instance, MLH۱ hypermethylation leads to MMR loss and genomic instability in sporadic MSI-high CRCs. The adenoma-carcinoma sequence illustrates CRC progression through stages: initiation (APC gene mutations forming early adenomas), progression (additional mutations in KRAS and DCC genes advancing adenomas), and malignant transformation (TP۵۳ inactivation and further genetic changes leading to invasive carcinoma). Angiogenesis, driven by the VEGF signaling pathway, provides tumors with nutrients and oxygen, facilitating metastasis, primarily to the liver and lungs. Metastasis involves detachment, tissue invasion, bloodstream entry, survival in circulation, and colonization of distant organs. Understanding the genetic mutations, molecular pathways, and epigenetic changes driving CRC is essential for developing targeted therapies and improving patient outcomes. Advances in genomic technologies and molecular biology enhance CRC diagnosis, monitoring, and treatment, promising better prognoses for patients worldwide.

کلیدواژه ها:

Colorectal cancer ، Molecular pathway ، Target therapy ، Angiogenesis ، Metastasis