title: Germline PIK3CA and AKT1 mutations in Cowden and Cowden-like syndromes.
abstract: Cowden syndrome (CS) is a difficult-to-recognize multiple hamartoma syndrome with high risks of breast, thyroid, and other cancers. Germline mutations in PTEN on 10q23 were found to cause 85% of CS when accrued from tertiary academic centers, but prospective accrual from the community over the last 12 years has revealed a 25% PTEN mutation frequency. PTEN is the phosphatase that has been implicated in a heritable cancer syndrome and subsequently in multiple sporadic cancers and developmental processes. PTEN antagonizes the AKT1/PI3K signaling pathway and has roles in cell cycle, migration, cell polarity, and apoptosis. We report that 8 of 91 (8.8%) unrelated CS individuals without germline PTEN mutations carried 10 germline PIK3CA mutations (7 missense, 1 nonsense, and 2 indels) and 2 (2.2%) AKT1 mutations. These mutations result in significantly increased P-Thr308-AKT and increased cellular PIP3. Our observations suggest that PIK3CA and AKT1 are CS susceptibility genes.
authors.affiliation: Genomic Medicine Institute and Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Mohammed S
authors.initials: MS
authors.lastname: Orloff
authors.forename: Xin
authors.initials: X
authors.lastname: He
authors.forename: Charissa
authors.initials: C
authors.lastname: Peterson
authors.forename: Fusong
authors.initials: F
authors.lastname: Chen
authors.forename: Jin-Lian
authors.initials: JL
authors.lastname: Chen
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Mester
authors.forename: Charis
authors.initials: C
authors.lastname: Eng
mesh_terms: D058534:Class I Phosphatidylinositol 3-Kinases; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006223:Hamartoma Syndrome, Multiple / Q000235:genetics*; D006801:Humans; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics*
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human