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Adult Leydig Cell Tumors of the Testis Caused by Germline Fumarate Hydratase Mutations

Molecular and Population Genetics Laboratory (L.G.C.-C., N.A.A., P.J.P., A.M.J., E.B., N.W., I.P.M.T.) and Histopathology Unit and In Situ Hybridisation Service (R.P.), London Research Institute, Cancer Research UK, London WC2A 3PX, United Kingdom; Department of Pathology and Microbiology, Division of Histopathology, Bristol Royal Infirmary (M.P.), Bristol BS2 8HW, United Kingdom; Department of Pathology, University College Hospital (A.F.), London WC1E 6JJ, United Kingdom; Department of Pathology, Kings College Hospital (S.P.), London SE5 9RS, United Kingdom; Department of Histopathology, Nottingham City Hospital (I.E.), Nottingham NG5 1PB, United Kingdom; Department of Histopathology, Division of Investigative Science, Imperial College (M.A.E.-B.), London WI2 0NN, United Kingdom; and Department of Pathology, St. Bartholomew’s Hospital (D.M.B.), London EC1A 7BE, United Kingdom

Address all correspondence and requests for reprints to: Dr. Luis G. Carvajal-Carmona, Ph.D., Laboratory of Molecular and Population Genetics, London Research Institute, Cancer Research UK, London WC2A 3PX, United Kingdom. E-mail: luis.carvajal{at}cancer.org.uk.

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. 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.

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 (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.

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