Adult leydig cell tumors of the testis caused by germline fumarate hydratase mutations.
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.
Carvajal-Carmona
Luis G
LG
Laboratory of Molecular and Population Genetics, London Research Institute, Cancer Research UK, London WC2A 3PX, United Kingdom. luis.carvajal@cancer.org.uk.
Alam
N Afrina
NA
Pollard
Patrick J
PJ
Jones
Angela M
AM
Barclay
Ella
E
Wortham
Noel
N
Pignatelli
Massimo
M
Freeman
Alex
A
Pomplun
Sabine
S
Ellis
Ian
I
Poulsom
Richard
R
El-Bahrawy
Mona A
MA
Berney
Daniel M
DM
Tomlinson
Ian P M
IP
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
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