Hamartomatous polyposis syndromes: molecular genetics, neoplastic risk, and surveillance recommendations.
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.
Wirtzfeld
D A
DA
Division of Surgical Oncology, Roswell Park Cancer Institute, State University of New York at Buffalo, 14263, USA.
Petrelli
N J
NJ
Rodriguez-Bigas
M A
MA
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
D016212:Transforming Growth Factor beta