Functional Phosphodiesterase 11A Mutations May Modify the Risk of Familial and Bilateral Testicular Germ Cell Tumors
Open Access
- 1 July 2009
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 69 (13), 5301-5306
- https://doi.org/10.1158/0008-5472.can-09-0884
Abstract
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]Keywords
Other Versions
This publication has 20 references indexed in Scilit:
- The International Testicular Cancer Linkage Consortium: A clinicopathologic descriptive analysis of 461 familial malignant testicular germ cell tumor kindredUrologic Oncology, 2010
- Genetic aspects of testicular germ cell tumorsCell Cycle, 2008
- Cancer Risk in Male Factor-infertilityPlacenta, 2008
- Phosphodiesterase 11A (PDE11A) and Genetic Predisposition to Adrenocortical TumorsClinical Cancer Research, 2008
- Phosphodiesterase 11A Expression in the Adrenal Cortex, Primary Pigmented Nodular Adrenocortical Disease, and other Corticotropin-independent LesionsHormone and Metabolic Research, 2008
- Analysis of the DND1 gene in men with sporadic and familial testicular germ cell tumorsGenes, Chromosomes and Cancer, 2007
- Genome-wide linkage screen for testicular germ cell tumour susceptibility lociHuman Molecular Genetics, 2006
- Phosphodiesterase 11 (PDE11) regulation of spermatozoa physiologyInternational Journal of Impotence Research, 2005
- Testicular germ-cell tumours in a broader perspectiveNature Reviews Cancer, 2005
- Localization to Xq27 of a susceptibility gene for testicular germ-cell tumoursNature Genetics, 2000