Inactivation of both alleles of the DPC4/SMAD4 gene in advanced colorectal cancers: identification of seven novel somatic mutations in tumors from Japanese patients

SMAD4 as a Prognostic Marker in Colorectal Cancer

“…Although DCC and SMAD2 have been suggested to be the target for most of the deletions in chromosome 18q observed in colorectal tumors (3 -5), there has been increasing interest in SMAD4 as a potential target gene. SMAD4 mutations have been linked to juvenile polyposis, a colorectal cancer predisposition syndrome (9), and frequent point mutations have been observed in sporadic colorectal tumors (11,12), suggesting that this gene is an important target for 18q deletions.…”

“…TGF-h signaling is an important regulator of proliferation, differentiation, and apoptosis with a key role in nontransformed human colon epithelium homeostasis (33 -35). SMAD4 has recently attracted considerable interest as a prime candidate target gene for the 18q deletions because of recent data linking mutations in this gene to sporadic and familial colorectal cancer (9,11,12).…”

“…SMAD4 mutations have recently been shown to be associated with the occurrence of juvenile polyposis, an autosomal dominant syndrome predisposing to hamartomatous polyps and colorectal cancer (9, 10). In addition, frequent somatic mutations have been found in human colorectal tumors in several studies, further suggesting an important role for this gene in colorectal carcinogenesis (11,12). Moreover, animal studies have shown that SMAD4 inactivation is involved in the malignant transformation of gastrointestinal adenomas (13) and a reduction in SMAD4 mRNA levels has been observed during tumor progression (14).…”

“…Although DCC and SMAD2 have been suggested to be the target for most of the deletions in chromosome 18q observed in colorectal tumors (3 -5), there has been increasing interest in SMAD4 as a potential target gene. SMAD4 mutations have been linked to juvenile polyposis, a colorectal cancer predisposition syndrome (9), and frequent point mutations have been observed in sporadic colorectal tumors (11,12), suggesting that this gene is an important target for 18q deletions.Because 18q deletions have been shown to be of prognostic significance for a subset of colorectal patients with locally advanced disease, we decided to investigate the potential of SMAD4 protein levels as a marker of prognosis in Dukes C colorectal cancer patients using immunohistochemistry. To this end, we constructed a tissue microarray containing triplicate tumor samples from all 86 Dukes C patients entered in this study.…”

Identification of the Modifier of Min 2 (Mom2) Locus, a New Mutation That Influences Apc-Induced Intestinal Neoplasia

“…Chromosome 18q21 is a region frequently found to undergo LOH in human colorectal tumors (Takagi et al 1996;Thiagalingam et al 1996). At least two genes in this region have been shown to result in intestinal neoplasia when cells undergo LOH, namely Smad2 and Smad4 (Koyama et al 1999;Miyaki et al 1999b;Tarafa et al 2000;Xu et al 2000). In addition, inheritance of an inactivating mutation in SMAD4 is responsible for a subset of the juvenile polyposis disorders (Howe et al 1998).…”