title: Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome.
abstract: Cowden disease (CD) is an autosomal dominant cancer predisposition syndrome associated with an elevated risk for tumours of the breast, thyroid and skin. Lhermitte-Duclos disease (LDD) cosegregates with a subset of CD families and is associated with macrocephaly, ataxia and dysplastic cerebellar gangliocytomatosis. The common feature of these diseases is a predisposition to hamartomas, benign tumours containing differentiated but disorganized cells indigenous to the tissue of origin. Linkage analysis has determined that a single locus within chromosome 10q23 is likely to be responsible for both of these diseases. A candidate tumour suppressor gene (PTEN) within this region is mutated in sporadic brain, breast and prostate cancer. Another group has independently isolated the same gene, termed MMAC1, and also found somatic mutations throughout the gene in advanced sporadic cancers. Mutational analysis of PTEN in CD kindreds has identified germline mutations in four of five families. We found nonsense and missense mutations that are predicted to disrupt the protein tyrosine/dual-specificity phosphatase domain of this gene. Thus, PTEN appears to behave as a tumour suppressor gene in the germline. Our data also imply that PTEN may play a role in organizing the relationship of different cell types within an organ during development.
authors.affiliation: Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
authors.forename: D
authors.initials: D
authors.lastname: Liaw
authors.forename: D J
authors.initials: DJ
authors.lastname: Marsh
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.forename: P L
authors.initials: PL
authors.lastname: Dahia
authors.forename: S I
authors.initials: SI
authors.lastname: Wang
authors.forename: Z
authors.initials: Z
authors.lastname: Zheng
authors.forename: S
authors.initials: S
authors.lastname: Bose
authors.forename: K M
authors.initials: KM
authors.lastname: Call
authors.forename: H C
authors.initials: HC
authors.lastname: Tsou
authors.forename: M
authors.initials: M
authors.lastname: Peacocke
authors.forename: C
authors.initials: C
authors.lastname: Eng
authors.forename: R
authors.initials: R
authors.lastname: Parsons
mesh_terms: D001943:Breast Neoplasms / Q000175:diagnosis / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D016147:Genes, Tumor Suppressor / Q000235:genetics*; D018095:Germ-Line Mutation; D006223:Hamartoma Syndrome, Multiple / Q000235:genetics*; D006801:Humans; D008297:Male; D051059:PTEN Phosphohydrolase; D010375:Pedigree; D010744:Phosphoric Monoester Hydrolases; D011110:Polymorphism, Genetic; D017027:Protein Tyrosine Phosphatases / Q000235:genetics*; D025521:Tumor Suppressor Proteins
chemical_list: D025521:Tumor Suppressor Proteins; D010744:Phosphoric Monoester Hydrolases; D017027:Protein Tyrosine Phosphatases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human