Mutations in the SMAD4/DPC4 gene in juvenile polyposis.

Familial juvenile polyposis is an autosomal dominant disease characterized by a predisposition to hamartomatous polyps and gastrointestinal cancer. Here it is shown that a subset of juvenile polyposis families carry germ line mutations in the gene SMAD4 (also known as DPC4), located on chromosome 18q21.1, that encodes a critical cytoplasmic mediator in the transforming growth factor-beta signaling pathway. The mutant SMAD4 proteins are predicted to be truncated at the carboxyl-terminus and lack sequences required for normal function. These results confirm an important role for SMAD4 in the development of gastrointestinal tumors.

[1]  K. Lunetta,et al.  Exclusion of PTEN and 10q22-24 as the susceptibility locus for juvenile polyposis syndrome. , 1997, Cancer research.

[2]  J. Newsome,et al.  Familial juvenile polyposis coli. A clinical and pathologic study of a large kindred. , 1982, Gastroenterology.

[3]  Scott E. Kern,et al.  DPC4, A Candidate Tumor Suppressor Gene at Human Chromosome 18q21.1 , 1996, Science.

[4]  G. Lenoir,et al.  PTEN germ-line mutations in juvenile polyposis coli , 1998, Nature Genetics.

[5]  Hiroyuki Miyoshi,et al.  Intestinal Tumorigenesis in Compound Mutant Mice of both Dpc4(Smad4) and Apc Genes , 1998, Cell.

[6]  K. Franssila,et al.  Familial juvenile polyposis coli; increased risk of colorectal cancer. , 1984, Gut.

[7]  Wei Zhang,et al.  Induction of p21waf1 expression and growth inhibition by transforming growth factor beta involve the tumor suppressor gene DPC4 in human pancreatic adenocarcinoma cells. , 1997, Cancer research.

[8]  Kathleen R. Cho,et al.  The DCC gene: structural analysis and mutations in colorectal carcinomas. , 1994, Genomics.

[9]  Hanlee P. Ji,et al.  Molecular classification of the inherited hamartoma polyposis syndromes: clearing the muddied waters. , 1998, American journal of human genetics.

[10]  Scott E. Kern,et al.  Evaluation of candidate tumour suppressor genes on chromosome 18 in colorectal cancers , 1996, Nature Genetics.

[11]  Kathleen R. Cho,et al.  DPC4 gene in various tumor types. , 1996, Cancer research.

[12]  Irene L Andrulis,et al.  MADR2 Maps to 18q21 and Encodes a TGFβ–Regulated MAD–Related Protein That Is Functionally Mutated in Colorectal Carcinoma , 1996, Cell.

[13]  C. Moskaluk,et al.  Genomic Sequencing of DPC4 in the Analysis of Familial Pancreatic Carcinoma , 1997, Diagnostic molecular pathology : the American journal of surgical pathology, part B.

[14]  C. Cordon-Cardo,et al.  DNA extraction from paraffin-embedded tissues using a salting-out procedure: a reliable method for PCR amplification of archival material. , 1997, Histology and histopathology.

[15]  Yigong Shi,et al.  A structural basis for mutational inactivation of the tumour suppressor Smad4 , 1997, Nature.

[16]  R. Lotan,et al.  DPC4, a candidate tumor suppressor gene, is altered infrequently in head and neck squamous cell carcinoma. , 1996, Cancer research.

[17]  J. Wrana,et al.  MAD-related proteins in TGF-β signalling , 1996 .

[18]  Y. Takagi,et al.  Somatic alterations of the DPC4 gene in human colorectal cancers in vivo. , 1996, Gastroenterology.

[19]  Hong Sun,et al.  TEP1, encoded by a candidate tumor suppressor locus, is a novel protein tyrosine phosphatase regulated by transforming growth factor beta. , 1997, Cancer research.

[20]  Jing Li,et al.  Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome , 1997, Nature Genetics.

[21]  J. Massagué,et al.  Partnership between DPC4 and SMAD proteins in TGF-β signalling pathways , 1996, Nature.