Pancolonic chromosomal instability precedes dysplasia and cancer in ulcerative colitis

Patients with long-standing ulcerative colitis (UC) are at increased risk f or colon cancer. These cancers are thought to arise from preexisting dyspla sia in a field of abnormal cells that often exhibits aneuploidy and p53 abn ormalities. Using dual color fluorescence in situ. hybridization with centr omere probes and locus-specific arm probes for chromosomes 8, 11, 17, and 1 8, we demonstrate that chromosomal instability (CIN) is present throughout the colon of UC patients with high-grade dysplasia or cancer. Ln rectal bio psies that were negative for dysplasia, abnormalities in chromosomal arms, especially losses, mere most common, whereas centromere gains were most com mon in dysplasia and cancer, The frequency and type of abnormalities varied between the chromosomes examined; chromosome 8 was the least affected, and 17p loss was found to be an early and frequent event. Chromosomal arm inst ability showed 100% sensitivity and specificity for distinguishing control biopsies from histologically negative rectal biopsies from these UC patient s, raising the possibility that a screen for CIN might detect the subset of UC patients who are at greatest risk for development of dysplasia and canc er. These results suggest that dysplasia and cancer in UC arise front a pro cess of CIN that affects the entire colon; this may provide the mutator phe notype that predisposes to loss of tumor suppressor genes and evolution of cancer.