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

Am J Hum Genet. 2013 Jan 10;92(1):76-80. doi: 10.1016/j.ajhg.2012.10.021. Epub 2012 Dec 13.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Class I Phosphatidylinositol 3-Kinases
  • Genetic Predisposition to Disease
  • Germ-Line Mutation
  • Hamartoma Syndrome, Multiple / genetics*
  • Humans
  • PTEN Phosphohydrolase
  • Phosphatidylinositol 3-Kinases / genetics*
  • Proto-Oncogene Proteins c-akt / genetics*


  • Phosphatidylinositol 3-Kinases
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CA protein, human
  • AKT1 protein, human
  • Proto-Oncogene Proteins c-akt
  • PTEN Phosphohydrolase
  • PTEN protein, human