Cowden syndrome (CS) is an autosomal
dominant disorder characterized by multiple
hamartomas and a risk of breast and thyroid
The great majority of tumors, including
those of the thyroid and breast, are benign. Up to
10 percent of affected individuals develop
nonmedullary thyroid carcinoma, and up to 50 percent
of affected females develop breast cancer.
The pathognomonic hamartoma is the
trichilemmoma, a benign tumor of the infundibulum of
the hair follicle.
The susceptibility gene for CS is a
tumor-suppressor gene as evidenced by loss of
heterozygosity in the PTEN region
of 10q23 in various tumors and by transfection.
The CS gene PTEN was
isolated by a combination of genetic mapping
analyses, somatic genetics, and a candidate gene
approach. PTEN, located on 10q23.3,
encodes a 403-amino acid protein, which contains a
phosphatase signature motif and has sequences
homologous to tensin.
PTEN is a dual-specificity lipid
phosphatase. PTEN is the 3-phosphatase for
phosphotidylinositol-3,4,5-triphosphate and, hence,
coordinately regulates the cell survival factor
PKB/Akt via the PI3 kinase signaling pathway.
Germ line mutations in PTEN have been found in CS
families as well as in the related but distinct
hamartoma disorder Bannayan-Ruvalcaba-Riley
syndrome. These mutations result in predicted
protein truncation or likely loss of function, hence
supporting its predicted function as a tumor
Somatic mutations of PTEN occur in a broad spectrum of
sporadic tumors, which is almost always biallelic.
However, alternate mechanisms of PTEN inactivation