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

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]

Analysis of genetic variants of phosphodiesterase 11A in acromegalic patients

“…Moreover, we found three other sequence variants, i.e. R804H, R867G, and M878V, associated with a reduced PDE activity in vitro, further suggesting that these variants, also present in the general population, could contribute to a genetic predisposition to endocrine lesions (10)(11)(12). Contrary to what has been reported in adrenal and testicular tumors, we did not detect any nonsynonymous substitutions in GAF A and GAF B, the cGMP binding domain of the enzyme.…”

“…The most frequent missense variation found in acromegalic patients and in controls was the Y272C substitution, a relatively frequent polymorphism listed in the databases. Although frequent in the general population, it has been recently reported that when transfected in murine Leydig tumor cell line 1, this variant was associated with higher cAMP levels and lower PDE activity in comparison with the wild-type enzyme (12). Moreover, we found three other sequence variants, i.e.…”

“…Admittedly, although healthy subjects of this series were not affected with clinically relevant endocrine disease, the presence of individuals with very mild and unrecognizable endocrine alterations in the control group cannot be excluded. Taking into account these limitations that are common to the other association studies, the frequency of PDE11A variants in acromegalic patients (17%) was found to be slightly lower in comparison with that reported for both adrenocortical and bilateral testicular germ cell tumors (20%) (11,12).…”

“…The allelic variants c.1072-3 COT in intron 4, c.1263 AOC/p.E421E in exon 6, c.1577 TOC in intron 10, c.1626 AOG/p.A542A in exon 11, c.1644C26insGTTTATA in intron 11, and c.2758_2760 insTCC/p.S920ins in exon 23 have already been reported in literature (11,12), while others, i.e. c.1501K107 AOG in intron 9, c.1576C67 AOCCT in intron 10, c.2424K46 C/T in intron 19 have only been recorded in online polymorphism databases (www.ensembl.org).…”

“…Germline inactivating or missense mutations of PDE11A gene have been identified in individuals with ACTH-independent macronodular adrenocortical hyperplasia, adrenocortical adenomas, and cancers (9)(10)(11), suggesting that these defects may confer susceptibility to the development of adrenocortical lesions. More recently, inactivating germline mutations in PDE11A have also been implicated in familial and bilateral testicular germ cell tumor susceptibility (12).…”