Lauri A Aaltonen Stina Roth and Charis Eng 1 Introduction

Cowden syndrome is a rare dominantly inherited condition with predisposition to benign hamartomatous polyposis of the intestine, as well as malignant tumors of the breast and thyroid, and possibly some other cancer types. Other features include macrocephaly and dysplastic cerebellar gangliocytomatosis with ataxia, as well as predisposition to formation of trichilemmomas of the skin (1). The latter are tumors of the hair root sheath.

It should be noted that, according to the present knowledge and unlike the other hamartomatous polyposis syndromes juvenile polyposis and Peutz-Jeghers syndrome, Cowden disease does not confer a clearly increased risk of colon cancer. Indeed, in the only population-based study, the risk of colon cancer was 3% (2). The disease is so poorly recognized that it is difficult to estimate whether some risk is present; adenomatous polyps in Cowden disease have been described (3). Clinical data of at least two Cowden syndrome families is compatible with colon cancer predisposition (Eng, unpublished).

Recently germline mutations of tumor suppressor gene PTEN (also known as MMAC1 or TEP1), a tumor suppressor gene on 10q23.3, have been shown to underlie the disease (4). The gene was identified through deletion mapping in sporadic tumors (5-7). PTEN acts as a tumor suppessor by negatively regulating the PI3K/PKB/Akt signaling pathway (8).

Bannayan-Zonana (Bannayan-Riley-Ruvalcaba) syndrome, characterized by macrocephaly, pigmented macules of the glans penis and lipomas, in addition to hamartomatous intestinal polyposis (1), appears to be allelic to Cowden syndrome (9,10). Lhermitte-Duclos disease, which is an hamartomatous overgrowth of cerebellar tissue, is also associated with Cowden disease and

From: Methods in Molecular Medicine, vol. 50: Colorectal Cancer: Methods and Protocols Edited by: S. M. Powell © Humana Press Inc., Totowa, NJ

germline PTEN mutations (11). One report has associated PTEN mutations and juvenile polyposis (12) but this result has not been confirmed (13) and individuals with PTEN mutations should be considered as having Cowden disease, with increased risk of thyroid and breast cancer (14,15).

PTEN is a relatively small gene comprising nine exons and encoding 403 amino acids. Thus we recommend genomic sequencing as the method of choice in the setting of clinical molecular diagnostics. Appropriate genetic counseling must be given before testing. In research environment consequences of missense changes to the phosphatase function can be evaluated (16,17).

Somatic PTEN mutations or homozygous deletions have been detected in multiple sporadic tumor types. These include glioma (18) and melanoma (19), tumors of the endometrium (20-23), especially ones showing microsatellite instability (24), prostate (25-27), hepatocellular (28,29), thyroid (30), bladder (31), breast (32-34), colon (35), head and neck (36), and lung cancers (37), as well as leukemia (37), and B-cell non-Hodgkin's lymphomas (38,39).

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