Germline PIK3CA and AKT1 mutations in Cowden and Cowden-like syndromes

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.