[PDF][PDF] Germline PIK3CA and AKT1 mutations in Cowden and Cowden-like syndromes

MS Orloff, X He, C Peterson, F Chen, JL Chen… - The American Journal of …, 2013 - cell.com
MS Orloff, X He, C Peterson, F Chen, JL Chen, JL Mester, C Eng
The American Journal of Human Genetics, 2013cell.com
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 …
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.
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