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

Abstract

Deletions of chromosome band 18q21 appear with very high frequency in a variety of carcinomas, especially in colorectal cancer. Potent tumor suppressor genes located in this region encode transforming growth factor beta (TGF-beta) signal transducers SMAD2 and SMAD4, and inactivation of either one leads to impaired TGF-beta-mediated cell growth/apoptosis. Following the assignment 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 available for all four genes, SMAD4, SMAD2, and the nearby gene DCC showed high deletion rates (66%, 64%, and 59%, respectively), whereas SMAD7 was deleted in only 48% of the tumors. Unexpectedly, we found some gene duplications; SMAD7 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 most common combination (26% of all the tumors) consists of the simultaneous deletions of SMAD2 and SMAD4 associated with normal diploidy or even duplication of SMAD7. Since SMAD7 normally counteracts SMAD2 and SMAD4 in TGF-beta signaling, we hypothesize that the tumor might not benefit from simultaneous SMAD7 inactivation, thereby exerting selective pressure to retain or even to duplicate the SMAD7 gene.

HER2/Neu- and TAK1-mediated Up-regulation of the Transforming Growth Factor β Inhibitor Smad7 via the ETS Protein ER81

“…Because Smad7 can inhibit the anti-proliferative TGF-␤ signaling, Smad7 overexpression may be an additional mechanism by which cells progress on their path to a transformed phenotype. Consistently, overexpression of Smad7 has been noted in pancreatic and colon cancers (29,30).…”

The SCF Cdc4 ubiquitin ligase regulates calcineurin signaling through degradation of phosphorylated Rcn1, an inhibitor of calcineurin

“…Degradation of Mdm2 can stimulate the p53 pathway (36). In addition, inhibitory Smads, feedback inhibitors of TGF-␤ signaling, are overexpressed in some types of tumors (37,38) and are degraded by ubiquitination (39). Therefore, degradation of feedback inhibitors might be a fundamental strategy in various processes that control cell signals.…”

SMAD7 is a prognostic marker in patients with colorectal cancer

“…SMAD2, SMAD7 and DCC data were available for 197, 178 and 206 samples, respectively. The total of 264 patients comprises 164 individuals described in our previous study 15 and 100 additional patients.…”

“…We recently reported that the deletion frequency of SMAD7, significantly lower than those of SMAD2 or SMAD4, reflects the frequent association of SMAD2 and SMAD4 gene deletion with retention of the SMAD7 gene located in between. 15 In addition, we have also defined SMAD4 as a predictive marker for benefit of chemotherapy in patients with CRC, suggesting that integrity of this component of the TGF␤/BMP signaling pathway may also be a condition for efficiency of chemotherapy. 21 We aimed to test whether the deletion of 18q21 genes SMAD2 and SMAD7, plus the DCC gene 3 located nearby, would have a significant influence on the outcome of patients with CRC.…”

“…Conversely, TGF␤ has been shown to be a potent cell growth inhibitor 10 and apoptosis inducer on prostatic epithelial cell lines, 11 whereas most squamous carcinoma lines are refractory to this function. 12 More recently, the position of the gene for SMAD7 13 has been assigned to this region by in situ hybridization 14 and mapped between the SMAD2 and SMADH4 genes 15 within a 4-megabase (Mb) gene cluster. 16 SMADs form a family of structurally related signaling proteins initially described in Drosophila 17 and in C. elegans.…”