Adult leydig cell tumors of the testis caused by germline fumarate hydratase mutations

Luis Carvajal-Carmona, N. Afrina Alam, Patrick J. Pollard, Angela M. Jones, Ella Barclay, Noel Wortham, Massimo Pignatelli, Alex Freeman, Sabine Pomplun, Ian Ellis, Richard Poulsom, Mona A. El-Bahrawy, Daniel M. Berney, Ian P M Tomlinson

Research output: Contribution to journalArticlepeer-review

86 Scopus citations


Context: Leydig cell tumors (LCTs) are the most common non-germ-cell neoplasms of the testis. LCTs are often hormonally active and can result in precocious virilization or in adult feminization. Weidentified an LCT in an affected individual from a kindred with hereditary leiomyomatosis and renal cell cancer (HLRCC) and a germline fumarate hydratase (FH) mutation (N64T). Objective: Our objective was to investigate the role of FH mutations in predisposition to LCTs. Design: We tested for pathogenic effects of the N64T mutation and screened an additional 29 unselected adult LCTs for FH alterations. We also tested these LCTs for mutations in two genes, the LH/choriogonadotropin receptor (LHCGR) and the guanine nucleotide-binding protein α (GNAS) that had been implicated in LCT tumorigenesis. Results: No mutations were found in GNAS, and one tumor had a LHCGRsomatic substitution. In addition to the HLRCC case with the N64T germline FH mutation, we identified one other LCT with a previously unreported FH mutation (M411I). Both LCTs from these patients showed loss of the wild-type FH allele. Immunohistochemical and in situ hybridization analyses demonstrated activation of the hypoxia/angiogenesis pathway not only in the tumors belonging to the FH mutation carriers but also in several other mutation-negative LCTs. Conclusions: Our study shows that some LCTs are caused by FH mutations and represents one of the first reports of germline mutations in any type of adult testicular tumor.

Original languageEnglish (US)
Pages (from-to)3071-3075
Number of pages5
JournalJournal of Clinical Endocrinology and Metabolism
Issue number8
StatePublished - 2006
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology, Diabetes and Metabolism


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