Germline PTEN mutation Cowden syndrome: An underappreciated form of hereditary kidney cancer

Brian Shuch, Christopher J. Ricketts, Cathy D. Vocke, Takefumi Komiya, Lindsay A. Middelton, Eric C. Kauffman, Maria J. Merino, Adam R. Metwalli, Phillip Dennis, W. Marston Linehan

Research output: Contribution to journalArticlepeer-review


Purpose: Cowden syndrome is a hereditary cancer syndrome associated with a germline mutation in PTEN. Patients are predisposed to multiple malignancies including renal cell carcinoma. Materials and 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 genotypephenotype 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.

Original languageEnglish (US)
Pages (from-to)1990-1998
Number of pages9
JournalJournal of Urology
Issue number6
StatePublished - Dec 2013
Externally publishedYes


  • Carcinoma, renal cell
  • Genetic diseases, inborn
  • Hamartoma syndrome, multiple

ASJC Scopus subject areas

  • Urology


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