Genetic Mutations Identified for Cowden Syndrome

Scientists at the Cleveland Clinic (Cleveland, OH, USA) performed genetic sequencing on DNA from individuals with CS who have none of the known genetic alterations associated with CS. State-of-the-art technology was used to identify a high prevalence of mutations in the phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) and the alpha serine/threonine-protein kinase (AKT1) genes, which are involved in cancer-related signaling pathways.

Germline mutations in the phosphatase and tensin homolog (PTEN) gene were found to cause 85% of CS when data from tertiary academic centers was analyzed. However, prospective data 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.

The investigators found that 8 of 91 (8.8%) unrelated CS individuals without germline PTEN mutations carried 10 germline PIK3CA mutations and 2 (2.2%) had AKT1 mutations. These mutations result in significantly increased phosphorylation of AKT on the activation residue Thr308 (P-Thr308-AKT) and increased cellular phosphatidylinositol (3,4,5)-triphosphate (PIP3). These results suggest that PIK3CA and AKT1 are CS susceptibility genes.

Charis Eng, MD, PhD, who is the Founding Director of the Lerner Research Institute's Genomic Medicine Institute (Cleveland, OH, USA) said, “Gene-enabled risk assessment and management begins with the identification of all the genes that, when mutated, account for as many or all the individuals with a particular syndrome, in this case CS. We started with only PTEN, and now we know that succinate dehydrogenase complex, subunit B, iron sulfur (SDHB/D), killin, p53-regulated DNA replication inhibitor (KLLN), PIK3CA, and AKT1 account for CS. Each also brings differing risks of breast, thyroid, and other cancers, and so this discovery directly aids genetic counseling and clinical management.” Cowden syndrome is a rare autosomal dominant inherited disorder characterized by multiple tumor-like growths called hamartomas and an increased risk of certain forms of cancer. The study was published on December 13, 2012, in the American Journal of Human Genetics.

Related Links:
Cleveland Clinic
Lerner Research Institute's Genomic Medicine Institute