Aberrant expression of G1-phase cell cycle regulators in flat and exophytic adenomas of the human colon

(Background & Aims) under bar: The G1/S-phase controlling mechanism known a s the RE pathway is commonly deregulated in human malignancies. Here, the a bundance and localization of key components of the retinoblastoma (RB) path way were determined in exophytic and flat colorectal adenomas, (Methods) un der bar: Samples of normal colonic mucosa (n = 41) and flat (n = 45) and ex ophytic (n = 26) adenomas were examined immunohistochemically using antibod ies to cyclins D1, D2, D3, cyclin-dependent kinase (CDH) 4, retinoblastoma protein (pRB), and the CDK inhibitors p16(INK4a), p18(INK4c), and p19(INK4d ). (Results) under bar: In normal colonic epithelium, cyclin D2 was undetec table; expression of cyclin D1, CDK4, and pRB correlated with proliferation ; and p16, p18, p19, and cyclin D3 were most abundant in quiescent, differe ntiated cells. Adenomas showed elevated expression of cyclin D1 and pRB, fr equent induction of cyclin D2, and absence of p16, No obvious abnormalities were found for p18, p19, or cyclin D3, Overexpressed cyclin D2 was more co mmon among exophytic and pRB among flat adenomas, respectively. Elevated cy clin D1, D2, and CDK4 correlated with enhanced dysplasia. (Conclusions) und er bar: Aberrant expression of cyclins D1, D2, CDK4, p16, and pRB occur in significant subsets of exophytic and flat adenomas, particularly among case s with high-grade dysplasia. Such defects of the RB pathway may perturb cel l-cycle control and thereby contribute an early step in colorectal tumorige nesis.