title: Novel germline mutations in the PTEN tumour suppressor gene found in women with multiple cancers.
abstract: Germline mutations in PTEN can predispose people to Cowden syndrome (CS) and Bannayan-Ruvalcaba-Riley (BRR) syndrome, rare, autosomal dominantly inherited neoplastic disorders. To determine whether germline mutations in PTEN contribute to genetic predisposition to multiple primary tumours within the general population, we conducted a nested case-control study, among 32 826 members of the prospective Nurses' Health Study cohort; cases were women with more than one primary tumour at different anatomical sites. We screened all nine exons of PTEN and flanking intronic splice sites for all 103 eligible cases using SSCP and sequencing. We observed two novel germline heterozygous missense mutations in exon 5 in five of the cases; three were V119L and two were V158L. Neither mutation was observed in 115 controls free of diagnosed cancer (p = 0.02). Both mutants showed partial tumour suppressor activity when compared to wild type PTEN when transfected into a PTEN null breast cancer cell line. The phenotype was cell line specific suggesting that genetic background affects growth suppression activity of the mutants. These data provide evidence that germline mutations in PTEN may be a more frequent predisposing factor for cancers in women than previously suggested.
authors.affiliation: Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, 181 Longwood Avenue, Boston, Massachusetts 02115, USA. devivo@channing.harvard.edu
authors.forename: I
authors.initials: I
authors.lastname: De Vivo
authors.forename: D M
authors.initials: DM
authors.lastname: Gertig
authors.forename: S
authors.initials: S
authors.lastname: Nagase
authors.forename: S E
authors.initials: SE
authors.lastname: Hankinson
authors.forename: R
authors.initials: R
authors.lastname: O'Brien
authors.forename: F E
authors.initials: FE
authors.lastname: Speizer
authors.forename: R
authors.initials: R
authors.lastname: Parsons
authors.forename: D J
authors.initials: DJ
authors.lastname: Hunter
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism; D016022:Case-Control Studies; D015331:Cohort Studies; D005091:Exons / Q000235:genetics; D005260:Female; D016147:Genes, Tumor Suppressor; D018095:Germ-Line Mutation; D006306:Health Surveys; D006801:Humans; D008875:Middle Aged; D009378:Neoplasms, Multiple Primary / Q000235:genetics*; D009726:Nurses; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics* / Q000378:metabolism; D010802:Phylogeny; D018807:Polymorphism, Single-Stranded Conformational; D017422:Sequence Analysis, DNA; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
chemical_list: D025521:Tumor Suppressor Proteins; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human