- Colorectal cancer (CRC) is one of the most common malignancies worldwide and a leading cause of cancer-related mortality.
- It arises from the epithelial lining of the colon or rectum and develops through a multistep process that involves the accumulation of genetic and epigenetic alterations. These changes transform normal mucosal cells into adenomas (benign polyps) and eventually into invasive carcinomas.
- The adenoma–carcinoma sequence, first described in the 1990s, remains a central model in understanding CRC pathogenesis, linking molecular events to the histological progression of the disease.
- At the molecular level, colorectal cancer is driven by genomic instability and dysregulated signaling pathways.
- The most common pathway, chromosomal instability (CIN), is characterized by mutations in tumor suppressors such as APC, leading to dysregulation of the Wnt/β-catenin signaling pathway, followed by mutations in KRAS, TP53, and SMAD4, which promote tumor growth, invasion, and resistance to apoptosis.
- Another subset of CRC arises through microsatellite instability (MSI), caused by defects in DNA mismatch repair (MMR) genes such as MLH1, MSH2, MSH6, or PMS2. MSI-high tumors tend to have a high mutational burden, distinct histological features, and a better prognosis, and they respond well to immunotherapy.
- A third pathway, CpG island methylator phenotype (CIMP), involves widespread promoter hypermethylation that silences tumor suppressor genes, often overlapping with MSI.
- CRC is strongly influenced by environmental and lifestyle factors, in addition to inherited predisposition.
- Diets high in red and processed meats, low physical activity, obesity, smoking, and alcohol consumption increase risk. Chronic inflammatory conditions such as ulcerative colitis and Crohn’s disease predispose to colorectal cancer through inflammation-driven genomic damage.
- Approximately 5–10% of CRCs arise from hereditary syndromes, the most notable being Lynch syndrome (hereditary nonpolyposis colorectal cancer, HNPCC), associated with germline MMR mutations, and familial adenomatous polyposis (FAP), caused by germline APC mutations, which leads to hundreds of colonic polyps and near-universal cancer development if untreated.
- Clinically, colorectal cancer often develops insidiously. Early stages are frequently asymptomatic, but as the disease progresses, patients may present with rectal bleeding, changes in bowel habits, abdominal pain, anemia, weight loss, or obstruction. The site of the tumor also influences symptoms: right-sided cancers often cause occult bleeding and anemia, while left-sided cancers more often cause changes in stool caliber and obstructive symptoms. Diagnosis is typically made through colonoscopy, which allows direct visualization and biopsy. Imaging modalities such as CT, MRI, and PET scans help in staging, which is crucial for treatment planning.
- Management of colorectal cancer depends on the stage at diagnosis. Surgical resection remains the cornerstone for localized disease, often combined with adjuvant chemotherapy in stage III and select stage II cases. Common chemotherapy regimens include fluoropyrimidines (5-fluorouracil or capecitabine) combined with oxaliplatin or irinotecan. For metastatic disease, targeted therapies such as EGFR inhibitors (cetuximab, panitumumab) and VEGF inhibitors (bevacizumab) are used, depending on the tumor’s molecular profile (e.g., KRAS/NRAS mutation status). In recent years, immunotherapy with checkpoint inhibitors (e.g., pembrolizumab, nivolumab) has shown remarkable efficacy in MSI-high colorectal cancers.
- Prevention and early detection are critical, as colorectal cancer is highly curable when diagnosed at an early stage. Screening programs—using colonoscopy, sigmoidoscopy, stool-based tests (FIT, FOBT), and DNA-based assays—have significantly reduced both incidence and mortality by allowing removal of precancerous polyps and early diagnosis. Guidelines recommend routine screening beginning at age 45–50 for average-risk individuals, with earlier screening for those with family history or genetic syndromes. Lifestyle modifications, such as diets rich in fiber, fruits, and vegetables, maintaining a healthy weight, regular exercise, and limiting red meat, alcohol, and tobacco, are also effective preventive strategies.
- In summary, colorectal cancer is a multifactorial disease shaped by genetic, epigenetic, environmental, and lifestyle influences. It progresses through well-characterized molecular pathways that guide both prognosis and therapy. Advances in molecular biology, screening, and targeted treatments have significantly improved survival, particularly for patients with early-stage disease or MSI-high tumors. Nevertheless, CRC remains a major global health burden, emphasizing the importance of prevention, early detection, and continued research into personalized therapeutic approaches.
