PTEN Mutations in Eight Spanish Families and One Brazilian Family with Cowden Syndrome

Abstract

Cowden syndrome is an autosomal dominant genodermatosis, characterized by the presence of multiple hamartomas in the skin, breast, thyroid, gastrointestinal tract, central nervous system, and an increased risk in developing breast and thyroid carcinomas. Over 80 germline mutations of the tumor suppressor gene PTEN, on chromosome 10q23, have been reported in more than 100 unrelated patients and families; however, questions regarding distribution of the mutations in populations from different geographic areas, and phenotypic expression are still unclear. In this study the results are reported of mutation analysis of PTEN in 13 families from Spain and one family of Brazilian origin with Cowden syndrome. PTEN germline mutations were detected in nine of them (64%). Five mutations were located in exon 5, one in exon 6, two in exon 7, and one in exon 8. Four of the mutations were novel. In another case, an identical change had been previously reported as a somatic mutation in an endometrial carcinoma. In one family, the patient presented a de novo mutation, which was not detected in his parents. In five patients, the detection of the PTEN germline mutation confirmed their condition, even in the absence of sufficient criteria to make the clinical diagnosis of Cowden syndrome.

Pten Loss in the Mouse Thyroid Causes Goiter and Follicular Adenomas: Insights into Thyroid Function and Cowden Disease Pathogenesis

“…Inherited PTEN mutations lead to Cowden disease, characterized by thyroid multinodular goiter and adenoma, and increased risk for thyroid cancer (18)(19)(20); in addition, activation of Akt (14) and gain-offunction mutations of PIK3CA, encoding the catalytic subunit of PI3K (13), have been correlated to thyroid carcinoma progression. PTEN subcellular distribution seems to shift from nuclear to cytoplasmic during neoplastic progression, before the dramatic reduction that characterizes advanced thyroid tumors (26) and, in follicular tumors, the localization of activated Akt is inversely correlated to the presence of PTEN in the nucleus (27).…”

“…In addition, deregulation of this cascade, through activation of PI3K and Akt and loss of PTEN expression, is frequently found in thyroid cancer (11)(12)(13)(14)(15)(16)(17). Finally, heterozygous mutation of PTEN causes Cowden disease, a dominant genetic syndrome whose characteristics include thyroid benign disorders, such as multinodular goiter and adenoma, and a 10% lifetime risk for developing thyroid cancer, mostly of the follicular type (18)(19)(20).…”

Immunohistochemical analysis of PTEN in endometrial carcinoma: a tissue microarray study with a comparison of four commercial antibodies in correlation with molecular abnormalities

“…PTEN is mutated in the germline of patients with a rare autosomal dominant cancer syndrome called Cowden's disease, and its variants. 16 However, PTEN is also frequently somatically mutated in tumors from various tissues. 2,3 Germline and somatic mutations in PTEN occur mostly in the phosphatase domain, between residues 122 and 132, in exon 5.…”

Mucocutaneous Neuromas

“…28,32 Despite these observations, neuromas are not mentioned as a manifestation of CS in the diagnostic criteria for the disorder, 2,34 in databases such as the Online Mendelian Inheritance in Man, 35 or in several recent review articles. 4,36,37 In addition to mucocutaneous neuromas, there are a few reports of solitary neurofibromas, 17,31,38,39 neurilemmomas, 40 and ganglions 10 in association with PHTS. Hypertrophy of cutaneous nerves is also a common incidental observation in skin biopsy specimens from patients with CS.…”

“…Staal et al 65 recently described a man with a germline mutation (Arg234Gln) in the 3Ј-encoded C2 domain of PTEN who developed brain tumors of multiple lineages (meningioma and glioma) but no other stigmata of PHTS. However, previous studies 1,4,7,31,46,66 failed to correlate particular germline PTEN mutations with specific phenotypic characteristics; clinical features often vary considerably within affected kindreds, and identical mutations have been described in individuals with CS and BRRS phenotypes. It is likely that modifying genes or cell type-specific RNA regulators have important effects on the types of tissues involved and the degree of severity of the manifestations (eg, hamartomas vs malignant neoplasms).…”