Abstract / Summary
Ulcerative colitis (UC) is associated with an increased risk of colorectal cancer, particularly in patients with long-standing and extensive disease. Although advances in medical therapy and surveillance have reduced colorectal cancer incidence, prolonged preservation of chronically inflamed colonic mucosa has increased the importance of understanding how cumulative inflammation promotes carcinogenesis. UC-associated neoplasia differs from sporadic colorectal cancer in its multifocality, pathological heterogeneity, and molecular evolution. Repeated inflammation, epithelial injury, and regeneration promote the accumulation of somatic and epigenetic alterations across histologically non-dysplastic mucosa, generating a cancerized field composed of genetically heterogeneous epithelial clones. Recent sequencing studies have shown that many clones selected in chronically inflamed mucosa harbor alterations that enhance adaptation to inflammatory stress but are not necessarily premalignant, indicating that field cancerization represents a dynamic evolutionary ecosystem rather than simple expansion of cancer-prone clones. Neoplastic progression requires further clonal selection as the selective environment shifts toward autonomous growth. Colitis-associated colorectal cancer is characterized by early TP53 alterations, a relatively late and less frequent involvement of APC, branching clonal evolution, and substantial copy-number alterations, particularly during progression from low- to high-grade dysplasia. Thus, colitis-associated carcinogenesis can be understood as a process in which chronic inflammation establishes a genetically altered field, followed by dynamic clonal selection and genomic evolution. Elucidating these processes may enable identification of high-risk fields and clones before invasive cancer develops and provide a biological basis for improved surveillance, risk stratification, and chemoprevention.