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-β) 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.
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Wirtzfeld, D.A., Petrelli, N.J. & Rodriguez-Bigas, M.A. Hamartomatous Polyposis Syndromes: Molecular Genetics, Neoplastic Risk, and Surveillance Recommendations. Ann Surg Oncol 8, 319–327 (2001). https://doi.org/10.1007/s10434-001-0319-7
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DOI: https://doi.org/10.1007/s10434-001-0319-7