Introduction: We have previously identified (using a whole-genome large scale SNP- screening approach) germline inactivating stop codon mutations of the PDE11A4 in patients with Cushing syndrome due to micronodular adrenal hyperplasia. PDE11A4 is a cAMP/cGMP phosphodiesterase.
Aim of the study: To investigate the role of PDE11A genetic alterations in a large cohort of ACT.
Materials and methods: Leukocyte DNA from 117 adrenocortical tumors (ACTs) were collected: 45 adrenocortical cancers (ACC), 43 adrenocortical adenomas (ACA) and 29 macronodular adrenal hyperplasia (AIMAH). Leukocyte DNAs from matched volunteers were collected by the same investigators after clinical examination to rule out endocrine tumors (control group). The PDE11A4 20 coding exons (exons 323) were amplified by polymerase chain reaction (PCR).
Results: One inactivating mutation was found in one non-secreting ACA (R307X); 21 missense mutations were also found: in 7 out 45 ACC (1 AA showed two differents missense mutations); in 7 of 29 AIMAHs, in 8 of 43 ACAs; no protein-truncating mutations were found in the controls. Two missense mutations (R804H and R867) were found in 5 ACTs and 5 of 192 controls, respectively; one missense mutation (A349T) was observed in one control. A higher frequency of missense and nonsense mutations in all 3 ACT groups than in controls groups were observed (16% vs 10% in ACC, 19% vs 10% in ACA and 24% vs 9% in AIMAH). This difference was significant in the AIMAH group, with an odds ratio of 3.53 (P=0.05). A significant difference between the ACC and the control groups for the synonymous polymorphism in exon 6 (E421E) was also found with an odds ratio of 2.1 (P=0.05).
Conclusion: PDE11A missense mutations and the E421E synonymous polymorphism are more frequently found in ACTs than in controls; PDE11A4 plays a role in genetic predisposition to adrenocortical tumorigenesis that extends beyond micronodular hyperplasias with which it was originally associated.