Missense mutations in PDE11A segregate with the disease in kindreds with testicular cancer. A. Horvath1, L. Korde2, R. Libe3, P. Osorio1, K. Tsang1, Y. Patronas1, L. Tschoukani1, L. Drori-Herishanu1, E. Remmers4, J. Bertherat3, M. Greene2, C. Stratakis1 1) NICHD, NIH, Bethesda, MD; 2) NCI, NIH, Bethesda, MD; 3) Institute Cochen, Paris, France; 4) NHGRI, NIH, Bethesda, MD.

   Inactivating mutations in the phosphodiesterase (PDE) 11A (PDE11A) have been implicated in predisposition to adrenocortical hyperplasia. PDE11A expression in testicular tissue were shown to be the second highest among the studied human tissues - slightly lower than in the prostate and significantly higher than in the adrenal cortex. Male sterility has been seen in the pde11a-/- mouse, and sterility in humans has been linked to TC. In this study, we sequenced the PDE11A gene coding region in 95 patients with testicular cancer (TC) from 40 unrelated families. We identified 8 different non-synonymous substitutions in a total of 23 patients from 13 families. Five of the variations were novel two we have reported before in patients with adrenocortical tumors and one was a common polymorphic variant. With the exception of one patient, all PDE11A missense variants coexisted with the disease status in the affected family members. We compared the frequency of these variants with that in a cohort of 200 unrelated controls who had been screened and found to be negative for adrenocortical diseases: only the two previously reported (R804H and R867G) that are known to be present in the general population were found in this control group. However, R804H and R867G were significantly more frequent among patients with TC than in controls (P=0.012); the combined frequency of nonsynonimous substitutions was significantly higher among TC patients (P=0.0004). Immunohistochemistry studies showed lack of expression of PDE11A protein in the tumor tissues of patients carriers of mutations in PDE11A. Ongoing studies investigate the expression of PDE11A in TC samples from these patients and the gonads of the pde11a-/- mouse. Our data suggest that PDE11A missense changes are perhaps among the many other genetic factors that may confer a predisposition to testicular tumors either within the context of the cAMP-signalling pathway or as players in a multisignaling system that controls germ cell develoment and/or tumorigenesis.