Combined copy status of 18q21 genes in colorectal cancer shows frequent retention of SMAD7

Deletions of chromosome band 18q21 appear with very high frequency in a var iety of carcinomas, especially in colorectal cancer, Potent tumor suppresso r genes located in this region encode transforming growth factor beta (TGF- beta) signal transducers SMAD2 and SMAD4, and inactivation of either one le ads to impaired TGF-beta -mediated cell growth/apoptosis. Following the ass ignment of SMAD7 to 18q21, we first refined the SMAD7 gene position within this region by genetically mapping SMAD7 between SMAD2 and SMAD4. Further, to compare the respective frequencies of genetic alterations of these three SMAD genes in colorectal cancer, we undertook a large-scale evaluation of the copy status of each of these genes on DNA samples from colorectal tumor biopsy material. Among a subset of 233 DNA samples for which data were ava ilable for all four genes, SMAD4, SMAD2, and the nearby gene DCC showed hig h deletion rates (66%, 64%, and 59%, respectively), whereas SMAD7 was delet ed in only 48% of the tumors. Unexpectedly, we found some gene duplications ; SMAD 7 appears to be more frequently amplified (10%) than the three other genes (4-7%). Compiled data for SMAD genes in each tumor show that the mos t common combination (26% of all the tumors) consists of the simultaneous d eletions of SMAD2 and SMAD4 associated with normal diploidy or even duplica tion of SMAD7. Since SMAD7 normally counteracts SMAD2 and SMAD4 in TGF-beta signaling, we hypothesize that the tumor might not benefit from simultaneo us SMAD7 inactivation, thereby exerting selective pressure to retain or eve n to duplicate the SMAD7 gene. (C) 2001 Wiley-Liss. Inc.