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Localization of the gene for Cowden disease to chromosome 10q22-23. Nat Genet

Department of Neurology, University Hospital Nijmegen, The Netherlands.
Nature Genetics (Impact Factor: 29.65). 06/1996; 13(1):114-6. DOI: 10.1038/ng0596-114
Source: PubMed

ABSTRACT Cowden disease (CD) (MIM 158350), or multiple hamartoma syndrome, is a rare autosomal dominant familial cancer syndrome with a high risk of breast cancer. Its clinical features include a wide array of abnormalities but the main characteristics are hamartomas of the skin, breast, thyroid, oral mucosa and intestinal epithelium. The pathognomonic hamartomatous features of CD include multiple smooth facial papules, acral keratosis and multiple oral papillomas. The pathological hallmark of the facial papules are multiple trichilemmomas. Expression of the disease is variable and penetrance of the dermatological lesions is assumed to be virtually complete by the age of twenty. Central nervous system manifestations of CD were emphasized only recently and include megalencephaly, epilepsy and dysplastic gangliocytomas of the cerebellum (Lhermitte-Duclos disease, LDD). Early diagnosis is important since female patients with CD are at risk of developing breast cancer. Other lesions include benign and malignant disease of the thyroid, intestinal polyps and genitourinary abnormalities. To localize the gene for CD, an autosomal genome scan was performed. A total of 12 families were examined, resulting in a maximum lod score of 8.92 at theta = 0.02 with the marker D10S573 located on chromosome 10q22-23.

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    • "Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) was originally described as a somatically mutated tumor-suppressor gene in brain, breast, and prostate cancers.[1] Germline loss-of-function PTEN mutations are responsible for Cowden, Bannayan-Riley-Ruvalcaba, and other syndromes, known collectively as the PTEN hamartoma tumor syndrome (PHTS).[2] [3] [4] [5] The autosomal-dominant and highly-penetrant PHTS conditions are characterized by a broad range of manifestations including macrocephaly, skin abnormalities, neurologic problems, and hamartomatous or ganglioneuromatous gastrointestinal polyposis.[6] "
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    ABSTRACT: Germline mutations in the PTEN tumor-suppressor gene cause autosomal-dominant conditions such as Cowden and Bannayan-Riley-Ruvalcaba syndromes with variable presentations, including hamartomatous gastrointestinal tumors, dermatologic abnormalities, neurologic symptoms, and elevated cancer risk. We describe a father and son with extensive hamartomatous gastrointestinal polyposis who both developed early-onset esophageal cancer. Exome sequencing identified a novel germline PTEN frameshift mutation (c.568_569insC, p.V191S_fs*11). In addition, a missense mutation of SMAD7 (c.115G>A, p.G39R) with an allele frequency of 0.3% in the Exome Variant Server was detected in both affected individuals. Fluorescence in-situ hybridization for PTEN in the resected esophageal cancer specimen demonstrated no PTEN copy loss in malignant cells, however, immunohistochemistry demonstrated loss of PTEN protein expression. While the risks of many cancers are elevated in the PTEN hamartoma tumor syndromes, esophageal adenocarcinoma has not been previously reported. Esophageal adenocarcinoma and extensive polyposis/ganglioneuromatosis could represent less-common features of these syndromes, potentially correlating with this novel PTEN frameshift and early protein termination genotype. Alternatively, because simultaneous disruption of both the PTEN and TGF-β/SMAD4 pathways is associated with development of esophageal cancer in a mouse model, and SMAD4 mutations cause gastrointestinal hamartomas in Juvenile Polyposis Syndrome, the SMAD7 mutation may represent an additional modifier of these individuals’ PTEN-mutant phenotype.
    Cancer Genetics 11/2014; DOI:10.1016/j.cancergen.2014.11.002 · 2.42 Impact Factor
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    • "Cowden syndrome is inherited in an autosomal dominant pattern and is characterised by the development of multiple hamartomas. This disease involves the loss of function of the phosphatase and tensin homolog (PTEN) in about 80-85% of affected individuals (Li et al., 1997; Liaw et al., 1997; Nelen et al., 1996). PTEN is a tumour suppressor gene that negatively regulates the protein kinase B (AKT) signaling pathway, which in turn inhibits the phosphorylation and regulation of key genes known to assist carcinogenesis by increasing cell proliferation and anti-apoptotic activity (Segrelles et al., 2002). "
    Skin Cancers - Risk Factors, Prevention and Therapy, 11/2011; , ISBN: 978-953-307-722-2
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    • "Thus, the N48K mutation renders a PTEN enzyme inactive, probably by altering the conformation of the nearby catalytic site and/or by making the accessibility to the phosphatidylinositol-3,4,5-triphosphate substrate di⁄cult. The recent observation of germline mutations of the PTEN gene in patients with CD provides strong evidence that PTEN functions as a tumor suppressor gene in this disease and related inherited disorders (Nelen et al, 1996; Liaw et al, 1997; Steck et al, 1997). It is well known that inactivation of a tumor suppressor gene generally involves independent inactivation of both alleles, usually by a point mutation of one allele and deletion of the other wild-type allele (Knudson et al, 1975). "
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    ABSTRACT: Cowden disease, also known as multiple hamartoma syndrome, is a rare disease inherited in an autosomal dominant pattern, which confers a high risk of developing breast and thyroid carcinomas. Mutations in PTEN, a tumor suppressor gene located on chromosome 10q23, have been identified in patients with Cowden disease. In this work, the direct sequencing of all coding regions of the PTEN gene led us to the identification of N48K, a new germline PTEN missense mutation, in a patient suffering from Cowden disease. The genetic analysis of 200 chromosomes from healthy individuals revealed that the variant was not common in our population. Moreover, by functional analysis we found that the ability of PTEN N48K mutant protein to inhibit the activation of the proto-oncogene PKB/Akt was impaired, supporting the involvement of N48K mutation in Cowden disease. Loss of heterozygosity using three microsatellites (D10S215, D10S541, and D10S564) and the complete sequence analysis of PTEN exons in breast and endometrial tumor samples from the same patient were also carried out in an attempt to identify additional PTEN somatic mutations. The lack of loss of heterozygosity or additional mutations in tumor samples suggests that abnormalities of the regulatory regions of the PTEN gene or haplo-insufficiency might occur in tumors from Cowden disease patients.
    Journal of Investigative Dermatology 01/2004; 121(6):1356-9. DOI:10.1111/j.1523-1747.2003.12638.x · 6.37 Impact Factor
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