p27 expression in inflammatory bower disease-associated neoplasia - Further evidence of a unique molecular pathogenesis

The cyclin-dependent kinase inhibitor p27 is a negative regulator of the tr ansition from G1 to S phase of the cell cycle, protects against inflammator y injury and promotes epithelial differentiation. Because p27 protein has b een shown to be abnormally expressed both in dysplasia associated with Barr ett's esophagus and in sporadic colorectal adenomas, we used immunohistoche mistry to evaluate p27 expression in inflammatory bowel disease (IBD)-assoc iated dysplasia and carcinomas. Normal, inflamed, and transitional mucose, sporadic adenomas, and sporadic colonic carcinomas were studied as controls . In normal colonic epithelium p27 expression was restricted to the superfi cial, terminally differentiated cells. In colitic and inflamed diverticular mucosa p27 was expressed in the base of the crypts in 86 and 70% of cases, respectively. Similarly, in transitional mucosa adjacent to sporadic carci nomas p27 was expressed in the base of the crypts in all cases. Strong p27 expression extended more frequently from the base of the crypts to superfic ial cells in IBD-associated dysplasia than in sporadic adenomas (P < 0.007) . Twenty of 20 (100%) IBD-associated carcinomas showed low p27 expression ( <50% nuclei positive) compared to 6 of 20 (30%) stage-matched sporadic colo rectal carcinomas (P < 0.001). We conclude (i) aberrant p27 protein express ion in inflamed and IBD-associated nondysplastic mucosa is indistinguishabl e from that found in transitional mucosa adjacent to sporadic carcinomas; ( ii) p27 is overexpressed in dysplastic lesions, perhaps as an attempt to co unterbalance proliferative stimuli; and (iii) IBD-associated colorectal car cinomas have significantly lower p27 expression, commonly associated with p oor prognosis, than stage-matched sporadic colorectal carcinomas. These fin dings further substantiate the existence of divergent molecular pathogeneti c pathways between these types of carcinomas and suggest an intrinsically m ore aggressive behavior of IBD-associated colon carcinomas compared to spor adic ones.