Molecular genetic alterations in carcinoma ex-pleomorphic adenoma: A putative progression model?

To determine the genetic changes associated with the development of carcinoma ex-pleomorphic adenoma (Ca Ex-PA), we analyzed 15 microsatellite loci at chromosome arms 8q, 12q, and 17p on DNA from 26 neoplasms (including 8 microdissected benign and malignant components), and 13 pleomorphic adenomas for comparison. Pleomorphic adenomas and the adenoma component of Ca Ex-PAs showed a higher incidence of loss of heterozygosity (LOH) at chromosome arms 8q (52%) and 12q (28%) than at 17p (14%) loci. In the carcinoma component, the combined LOH at chromosome arm 8q, 12q, and 17p regions was 69%, 50%, and 69%, respectively; within these chromosomal regions, 8q 11.23-q 12 (42%), 12q23-qter (39%), 17p13 (41%), and 17p11 (45%) loci manifested the highest incidence of LOH. Eight carcinomas (30.7%) showed loss at all three chromosomal arms tested. Of the eight microdissected Ca Ex- PAs analyzed, four adenoma and corresponding carcinoma components (50%) had the same LOH at 12q loci and additional LOH at 17p loci only in carcinomas. Chromosome arm 17p alterations correlated significantly with high disease stage and an increased proliferative rate in these tumors. Our results indicate that alterations at regions on chromosome arms 8q and/or 12q may constitute early events associated with pleomorphic adenomas; that LOH at 12q loci may identify a subset of adenoma with potential progression to carcinoma; that acquisition of additional alterations at chromosome arm 17p loci might represent an event preceding malignant transformation and progression; and that 8q, 12q, and 17p regions may harbor tumor suppressor genes involved in the genesis of PA and Ca Ex-PA.