Role of PTEN, a lipid phosphatase upstream effector of protein kinase B, in epithelial thyroid carcinogenesis.
Both benign and malignant thyroid disease are well-established components of Cowden syndrome (CS), an autosomal dominant disorder characterized by multiple hamartomas and breast cancer that may be considered a phakomatosis. The susceptibility gene for CS is PTEN, a tumor suppressor gene on 10q23.3 that encodes a lipid phosphatase that lies upstream of protein kinase B (Akt). Interestingly, Carney complex is also a phakomatosis where multiple endocrine neoplasias are prominent and thyroid cancer might be a rare component. One of its susceptibility genes is the regulatory subunit of protein kinase A. Over the course of the last four years, investigators have found the increasing clinical spectrum of syndromes characterized by germline loss-of-function PTEN mutation. In addition to CS, subsets of such disparate syndromes as Bannayan-Riley-Ruvalcaba syndrome, Proteus syndrome, and possibly VATER with hydrocephalus and megencephaly with autistic features have been found to have germline PTEN mutations. Paradoxically, somatic intragenic PTEN mutations were rare in uncultured primary epithelial thyroid tumors, although hemizygous deletion occurred in 10-20% of thyroid adenomas and carcinomas. However, with subsequent study, it was discovered that epigenetic silencing of PTEN and perhaps inappropriate subcellular compartmentalization were two novel mechanisms of PTEN inactivation pertinent in thyroid carcinogenesis. Ectopic expression studies in vitro have borne out the importance of PTEN in the pathogenesis of epithelial thyroid neoplasias.
Eng
Charis
C
Clinical Cancer Genetics and Human Cancer Genetics Programs, Comprehensive Cancer Center, and Division of Human Genetics, Department of Internal Medicine, The Ohio State University, Columbus, Ohio 43210, USA. eng.25@osu.edu
D017209:Apoptosis / Q000502:physiology; D004847:Epithelial Cells / Q000378:metabolism*; D016147:Genes, Tumor Suppressor; D006223:Hamartoma Syndrome, Multiple / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D009154:Mutation; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics* / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D013964:Thyroid Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism*
D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human