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Division of Surgical Oncology, Roswell Park Cancer Institute, State University of New York at Buffalo, Buffalo, New York.
Correspondence: Address correspondence and reprint requests to: Miguel Rodriguez-Bigas MD, FACS, Division of Surgical Oncology, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY, 14263; Fax: 716-845-3434; E-mail: miguel.rodriguez-bigas{at}roswellpark.org
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-ß) 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.
Key Words: Hamartomatous polyposis syndromes • Molecular genetics • Surveillance
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