Alteration of AKAP220, an upstream component of the Rb pathway, in oral carcinogenesis.

Few genes have been implicated in the development of oral cancer. In our study, we identified a novel gene in the Rb pathway that is frequently altered and overexpressed in oral tumors. Significantly, the alteration is also associated with early oral premalignant lesions (OPLs). This region was identified through a genomewide scan using randomly amplified polymorphic DNA (RAPD) PCR of 40 microdissected oral squamous cell carcinomas (SCCs). Recurrent gain of a approximately 400 bp signal was observed in multiple patients. This gain was localized to 13q14.11, a region frequently altered in multiple cancer types. Through microsatellite analysis, a 1.9 Mbp minimal region of alteration (MRA) was defined between D13S263 and D13S1227. Allelic imbalance (AI) in the MRA was present in only 28% of low-grade dysplasia, but strikingly increased with progression to 64% in high-grade dysplasia, plateauing at 61% in tumors, thus implicating this alteration in the early stages of disease development. Of the 3 genes residing within the MRA, Receptor Activator of NK-kappa-B Ligand (RANKL) and Diacylglycerol Kinase (DGKH) showed no change in expression levels in tumors compared to normal tissue. In contrast, 12 of 16 tumors showed significant overexpression of A-Kinase Anchoring Protein 220 (AKAP220). Since AKAP220 plays a role in regulating the Rb pathway, its dysregulation may contribute significantly to alterations in cell cycle regulation that facilitate progression of OPLs. (c) 2005 Wiley-Liss, Inc.