title: Hamartomatous polyposis syndromes: molecular genetics, neoplastic risk, and surveillance recommendations.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Surgical Oncology, Roswell Park Cancer Institute, State University of New York at Buffalo, 14263, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Wirtzfeld
authors.forename: N J
authors.initials: NJ
authors.lastname: Petrelli
authors.forename: M A
authors.initials: MA
authors.lastname: Rodriguez-Bigas
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D002471:Cell Transformation, Neoplastic; D003937:Diagnosis, Differential; D005260:Female; D016147:Genes, Tumor Suppressor / Q000235:genetics*; D018095:Germ-Line Mutation; D006223:Hamartoma Syndrome, Multiple / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D010375:Pedigree; D010580:Peutz-Jeghers Syndrome / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D017354:Point Mutation; D012307:Risk Factors; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics
chemical_list: D016212:Transforming Growth Factor beta