title: Germline PTEN mutation Cowden syndrome: an underappreciated form of hereditary kidney cancer.
abstract: OBJECTIVE
  Cowden syndrome is a hereditary cancer syndrome associated with a germline mutation in PTEN. Patients are predisposed to multiple malignancies including renal cell carcinoma.
  
  
  METHODS
  Patients with Cowden syndrome were evaluated as part of a clinical protocol. Those with a history of renal cell carcinoma underwent review of clinical features, tumor characteristics and family history. Renal tumors were evaluated for loss of heterozygosity.
  
  
  RESULTS
  Among 24 patients with Cowden syndrome 4 were identified with renal cell carcinoma (16.7%). Three patients had solitary tumors, 2 with papillary type I histology and 1 with clear cell histology. The fourth patient had bilateral, synchronous chromophobe tumors. No patients had a prior family history of renal cell carcinoma. All patients with renal cell carcinoma had dermatologic manifestations of Cowden syndrome and had macrocephaly. Loss of heterozygosity at the PTEN mutation was identified in 4 tumors (80%). No genotype-phenotype association was found, as the same mutation was identified in different renal cell carcinoma histologies.
  
  
  CONCLUSIONS
  Renal cell carcinoma is an underappreciated feature of Cowden syndrome. As most patients lack a prior family history or a distinctive renal cell carcinoma histology, recognition of the associated nonrenal features should target referral for genetic counseling. PTEN loss of heterozygosity is common in Cowden syndrome renal tumors. Because loss of PTEN can activate mTOR and mTOR inhibitors are Food and Drug Administration approved to treat renal cell carcinoma, these agents have clinical potential in renal cell carcinoma associated with Cowden syndrome.
authors.affiliation: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Brian
authors.initials: B
authors.lastname: Shuch
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Ricketts
authors.forename: Cathy D
authors.initials: CD
authors.lastname: Vocke
authors.forename: Takefumi
authors.initials: T
authors.lastname: Komiya
authors.forename: Lindsay A
authors.initials: LA
authors.lastname: Middelton
authors.forename: Eric C
authors.initials: EC
authors.lastname: Kauffman
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Merino
authors.forename: Adam R
authors.initials: AR
authors.lastname: Metwalli
authors.forename: Phillip
authors.initials: P
authors.lastname: Dennis
authors.forename: W Marston
authors.initials: WM
authors.lastname: Linehan
mesh_terms: D000328:Adult; D002292:Carcinoma, Renal Cell / Q000235:genetics*; D005260:Female; D006223:Hamartoma Syndrome, Multiple / Q000235:genetics*; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D010375:Pedigree
chemical_list: D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: BHD; Birt-Hogg-Dube; CS; CS associated renal cell carcinoma; CS-RCC; Cowden syndrome; HPRC; LOH; RCC; VHL; Von Hippel-Lindau; carcinoma; genetic diseases; hamartoma syndrome; hereditary papillary renal cell carcinoma; inborn; loss of heterozygosity; multiple; renal cell; renal cell carcinoma