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Alterations of Phosphodiesterases in Adrenocortical Tumors
Fady Hannah-Shmouni1, Fabio R Faucz1, Constantine A Stratakis1
1Program on Developmental Endocrinology and Genetics (PDEGEN), Section on Endocrinology and Genetics (SEGEN), National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH) , Bethesda, MD , USA.
Abstract:
Alterations in the cyclic (c)AMP-dependent signaling pathway have been implicated in the majority of benign adrenocortical tumors (ACTs) causing Cushing syndrome (CS). Phosphodiesterases (PDEs) are enzymes that regulate cyclic nucleotide levels, including cyclic adenosine monophosphate (cAMP). Inactivating mutations and other functional variants in PDE11A and PDE8B, two cAMP-binding PDEs, predispose to ACTs. The involvement of these two genes in ACTs was initially revealed by a genome-wide association study in patients with micronodular bilateral adrenocortical hyperplasia. Thereafter, PDE11A or PDE8B genetic variants have been found in other ACTs, including macronodular adrenocortical hyperplasias and cortisol-producing adenomas. In addition, downregulation of PDE11A expression and inactivating variants of the gene have been found in hereditary and sporadic testicular germ cell tumors, as well as in prostatic cancer. PDEs confer an increased risk of ACT formation probably through, primarily, their action on cAMP levels, but other actions might be possible. In this report, we review what is known to date about PDE11A and PDE8B and their involvement in the predisposition to ACTs.
Insights
Altered cyclic adenosine monophosphate (cAMP) signaling, particularly involving phosphodiesterases PDE11A and PDE8B, is linked to benign adrenocortical tumors (ACTs). These genetic variants increase the risk of developing ACTs and other cancers.
Area of Science:
- Endocrinology
- Molecular Biology
- Oncology
Background:
- Cyclic adenosine monophosphate (cAMP) signaling is crucial in adrenal function and implicated in benign adrenocortical tumors (ACTs) causing Cushing syndrome (CS).
- Phosphodiesterases (PDEs) regulate intracellular cAMP levels, and specific PDEs, PDE11A and PDE8B, are known to bind cAMP.
Purpose of the Study:
- To review the role of PDE11A and PDE8B in the predisposition to adrenocortical tumors (ACTs).
- To summarize current knowledge on PDE11A and PDE8B involvement in ACTs and other cancers.
Main Methods:
- Review of existing literature, including genome-wide association studies and genetic analyses of tumor samples.
- Analysis of genetic variants and expression patterns of PDE11A and PDE8B in various tumor types.
Main Results:
- Inactivating mutations and variants in PDE11A and PDE8B predispose individuals to ACTs, including micronodular and macronodular hyperplasia and cortisol-producing adenomas.
- PDE11A alterations are also found in testicular germ cell tumors and prostate cancer, suggesting broader roles for these PDEs in tumorigenesis.
Conclusions:
- PDE11A and PDE8B play a significant role in the development of ACTs, likely through their regulation of cAMP levels.
- Dysregulation of these phosphodiesterases represents a potential risk factor for multiple tumor types.
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