Functional Phosphodiesterase 11A Mutations May Modify the Risk of Familial and Bilateral Testicular Germ Cell Tumors
| Autor: | Joseph Greene, Maria Eleni Nikita, Larissa A. Korde, Yianna Patronas, Elaine F. Remmers, Marie Laure Raffin-Sanson, Jérôme Bertherat, Maria J. Merino, Paulo Osorio, Limor Drori-Herishanu, Jason Moran, Constantine A. Stratakis, Fabio R. Faucz, Kit Man Tsang, Anelia Horvath, Maria Nesterova, Rossella Libé, Mark H. Greene |
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| Rok vydání: | 2009 |
| Předmět: |
Adult
Male Nonsynonymous substitution Cancer Research medicine.medical_specialty Adolescent Population Testicular Germ Cell Tumor Biology Kidney Transfection White People Article Cell Line Male infertility Young Adult Germline mutation Gene Frequency Testicular Neoplasms 3' 5'-Cyclic-GMP Phosphodiesterases Risk Factors Internal medicine medicine Humans Age of Onset education Gene Allele frequency education.field_of_study Phosphoric Diester Hydrolases Genetic Variation Cancer Middle Aged Neoplasms Germ Cell and Embryonal medicine.disease National Cancer Institute (U.S.) United States Endocrinology Oncology Mutation |
| Zdroj: | Cancer Research. 69:5301-5306 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.can-09-0884 |
| Popis: | 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] |
| Databáze: | OpenAIRE |
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