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Functional Phosphodiesterase 11A Mutations May Modify the Risk of Familial and Bilateral Testicular Germ Cell Tumors

¹ Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development; ² Clinical Genetics Branch and ³ Laboratory of Pathology, National Cancer Institute; and ⁴ Genetics and Genomics Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland; ⁵ Institut National de la Sante et de la Recherche Medicale U567, and Institut Cochin, Centre National de la Recherche Scientifique UMR8104, Hôpital Cochin, Université Paris Descartes; ⁶ Institut National de la Sante et de la Recherche Medicale U567, Departement Endocrinologie, Metabolisme and Cancer, Institut Cochin, and Centre National de la Recherche Scientifique UMR8104, Paris, France; ⁷ Laboratory of Molecular Genetics, Pontificia Universidade Catolica do Parana, Curitiba, Brazil; ⁸ Hôpital Ambroise Paré, Department of Endocrinology, Boulogne sur Seine, France; and ⁹ Université de Versailles, St. Quentin en Yvelines, France

Requests for reprints: Anelia Horvath, Program on Developmental Endocrinology and Genetics (PDEGEN), Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, 10 Center Drive, CRC, Room 1-3330, Bethesda, MD 20892. Phone: 301-402-1998; Fax: 301-402-0574; E-mail: horvatha{at}mail.nih.gov.

Key Words: Phosphodiesterase (PDE) • testicular cancer • TGCT • mutations • cAMP

Inactivating germline mutations in phosphodiesterase 11A (PDE11A) have been implicated in adrenal tumor susceptibility. PDE11A is highly expressed in endocrine steroidogenic tissues, especially the testis, and mice with inactivated Pde11a exhibit male infertility, a known testicular germ cell tumor (TGCT) risk factor. We sequenced the PDE11A gene-coding region in 95 patients with TGCT from 64 unrelated kindreds. We identified 8 nonsynonymous substitutions in 20 patients from 15 families: four (R52T, F258Y, G291R, and V820M) were newly recognized, three (R804H, R867G, and M878V) were functional variants previously implicated in adrenal tumor predisposition, and one (Y727C) was a known polymorphism. We compared the frequency of these variants in our patients to unrelated controls that had been screened and found negative for any endocrine diseases: only the two previously reported variants, R804H and R867G, known to be frequent in general population, were detected in these controls. The frequency of all PDE11A-gene variants (combined) was significantly higher among patients with TGCT (P = 0.0002), present in 19% of the families of our cohort. Most variants were detected in the general population, but functional studies showed that all these mutations reduced PDE activity, and that PDE11A protein expression was decreased (or absent) in TGCT samples from carriers. This is the first demonstration of the involvement of a PDE gene in TGCT, although the cyclic AMP signaling pathway has been investigated extensively in reproductive organ function and their diseases. In conclusion, we report that PDE11A-inactivating sequence variants may modify the risk of familial and bilateral TGCT. [Cancer Res 2009;69(13):5301–6]

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