transforming-growth-factor-beta and Hamartoma-Syndrome--Multiple

Juvenile polyps are hamartomatous polyps found primarily in infants and children, and in association with juvenile polyposis (JP; OMIM #174900), Cowden syndrome (CS; OMIM #158350), and Bannayan-Riley-Ruvalcaba syndrome (BRRS; OMIM# 153480). Although solitary juvenile polyps are benign lesions, when present in JP patients they may lead to gastrointestinal cancers. Germline mutations in MADH4 and BMPR1A predispose to JP, and both genes are involved in TGF-beta superfamily signaling pathways. In CS and BRRS, juvenile polyps are a less consistent feature, and CS patients are at risk for breast and thyroid cancers. Mutations of the tumor suppressor gene PTEN have been found in the germline of both CS and BRRS patients. Despite different underlying genetic mechanisms, these and other syndromes share the same phenotypic feature of juvenile polyps.

Topics: Animals; Child; Child, Preschool; DNA-Binding Proteins; Genetic Predisposition to Disease; Germ-Line Mutation; Hamartoma Syndrome, Multiple; Humans; Infant; Intestinal Polyposis; Intestinal Polyps; Mice; Phosphoric Monoester Hydrolases; PTEN Phosphohydrolase; Smad4 Protein; Syndrome; Trans-Activators; Transforming Growth Factor beta; Tumor Suppressor Proteins

Hamartomatous polyposis syndromes are characterized by an overgrowth of cells or tissues native to the area in which they normally occur. Juvenile polyposis syndrome (JPS) results from germ-line mutations in the SMAD-4 gene (18q21.1) that encodes for an enzyme involved in transforming growth factor beta(TGF-beta) signal transduction. The increased neoplastic risk may result from SMAD-4 mutations in the stromal component, which stimulate epithelial dysplasia and progression to invasive malignancy. Peutz-Jeghers syndrome (PJS) is associated with germ-line mutations in the LKB1 gene (19p13.3) that encodes a multifunctional serine-threonine kinase. These mutations occur in the epithelial component, suggesting a direct tumor suppressor effect. Patients are at an increased risk of intestinal and extraintestinal malignancies, including breast, pancreatic, ovarian, testicular, and cervical cancer. Cowden's disease is associated with germ-line mutations in the PTEN gene (10q22-23) and an increased risk of breast and thyroid malignancies. Ruvalcaba-Myhre-Smith syndrome is less common; controversy suggests that it may represent a variant of Cowden's disease.. Genetic alterations underlying hamartomatous polyposis syndromes are diverse. Carcinogenesis may result from either germ-line mutations in the stroma (JPS) or as a direct result of functional deletion of tumor suppressor genes (PJS). Diagnosis depends on clinical presentation and patterns of inheritance within families. Suggested surveillance guidelines for the proband and first-degree relatives are outlined.

Topics: Adenomatous Polyposis Coli; Adolescent; Adult; Age of Onset; Aged; Cell Transformation, Neoplastic; Diagnosis, Differential; Female; Genes, Tumor Suppressor; Germ-Line Mutation; Hamartoma Syndrome, Multiple; Humans; Male; Middle Aged; Neoplasm Invasiveness; Pedigree; Peutz-Jeghers Syndrome; Point Mutation; Risk Factors; Signal Transduction; Transforming Growth Factor beta

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.

Topics: Cell Membrane; Cell Nucleus; Chromosome Mapping; Chromosomes, Human, Pair 18; Colorectal Neoplasms; DNA-Binding Proteins; Female; Frameshift Mutation; Gastrointestinal Neoplasms; Genes, DCC; Genes, Tumor Suppressor; Genetic Predisposition to Disease; Germ-Line Mutation; Hamartoma Syndrome, Multiple; Humans; Intestinal Polyps; Male; Pedigree; Polymerase Chain Reaction; Sequence Deletion; Signal Transduction; Smad4 Protein; Trans-Activators; Transforming Growth Factor beta