title: Adult leydig cell tumors of the testis caused by germline fumarate hydratase mutations.
abstract: BACKGROUND
  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. We identified 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.
  
  
  METHODS
  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 alpha (GNAS) that had been implicated in LCT tumorigenesis.
  
  
  RESULTS
  No mutations were found in GNAS, and one tumor had a LHCGR somatic 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.
authors.affiliation: Laboratory of Molecular and Population Genetics, London Research Institute, Cancer Research UK, London WC2A 3PX, United Kingdom. luis.carvajal@cancer.org.uk.
authors.forename: Luis G
authors.initials: LG
authors.lastname: Carvajal-Carmona
authors.forename: N Afrina
authors.initials: NA
authors.lastname: Alam
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Pollard
authors.forename: Angela M
authors.initials: AM
authors.lastname: Jones
authors.forename: Ella
authors.initials: E
authors.lastname: Barclay
authors.forename: Noel
authors.initials: N
authors.lastname: Wortham
authors.forename: Massimo
authors.initials: M
authors.lastname: Pignatelli
authors.forename: Alex
authors.initials: A
authors.lastname: Freeman
authors.forename: Sabine
authors.initials: S
authors.lastname: Pomplun
authors.forename: Ian
authors.initials: I
authors.lastname: Ellis
authors.forename: Richard
authors.initials: R
authors.lastname: Poulsom
authors.forename: Mona A
authors.initials: MA
authors.lastname: El-Bahrawy
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Berney
authors.forename: Ian P M
authors.initials: IP
authors.lastname: Tomlinson
mesh_terms: D001483:Base Sequence; D002864:Chromogranins; D018076:DNA, Complementary / Q000737:chemistry; D005649:Fumarate Hydratase / Q000235:genetics*; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000032:analysis; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007984:Leydig Cell Tumor / Q000737:chemistry / Q000235:genetics*; D008297:Male; D008958:Models, Molecular; D009389:Neovascularization, Pathologic; D011974:Receptors, LH / Q000235:genetics; D017422:Sequence Analysis, DNA; D013736:Testicular Neoplasms / Q000737:chemistry / Q000235:genetics*; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis
chemical_list: D002864:Chromogranins; D018076:DNA, Complementary; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011974:Receptors, LH; D042461:Vascular Endothelial Growth Factor A; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs; D005649:Fumarate Hydratase