Background: Mutations in the AlP gene have been described in association with familial pituitary tumor syndromes (1). Studies of nonpituitary tumors concomitantly occurring in AIPgermline mutation carriers still need to be assessed for a better understanding of tumoral susceptibility to AlP defects.
Aim: To investigate whether the AlP gene was involved in the tumorigenesis of a large and virilizing adrenocortical carcinoma diagnosed in a female acromegalic patient harboring the R81 X germline mutation in the AlP gene. Design: Somatic AlP status was assessed through analysis of 11 q13-AIP flanking microsatellite markers. The AlP protein level in the tumor was verified by immunohistochemical staining.
Results: Using the 11 q13 polymorphic markers, we found that the AlP wild type allele was lost in DNA from tumor samples from the patient's adrenocortical carcinoma (as well as in the somatotropinoma of her acromegalic daughter, who inherited the AlP mutation). Immunohistochemical staining of a normal pituitary gland showed pituitary cells displaying strong cytoplasmic staining for AlP, while no AlP protein expression was detected in the patient's adrenocortical carcinoma cells using the same procedure.
Discussion: In the current study, we present the first indication that AlP mutation carriers may develop adrenocortical tumors. This expands the spectrum of the clinical features thus far associated with AlP defects. During the ongoing study, it has been shown by another research group thatthe R81X-AIP mutation blocks AlP interaction with PDE4A (a cAMP-specific phosphodiesterase) and is likely to cause anomalous intracellular cAMP signaling (2). Taken together, these data suggest that AlP may be a new example of a susceptibility gene for both pituitary and adrenal tumorigenesis by dysregulating cAMP intracellular signaling.
References:
1. Vierimaa 0, et al. Pituitary adenoma predisposition caused by germline mutations in the AlP gene. Science 2006 261228-30.
2. Leontiou CA, et al. The role of the AlP gene in familial and sporadic pituitary adenomas. Journal of Clinical Endocrinology and Metabolism 2008
Support: RAT. is recipient of Coordena\ao de Aperfei\oamento de Pessoal de Nivel Superior (CAPES) PhD fellowship. D.M.L is recipient of Funda\ao Faculdade de Medicina (FFM) pas-doctoral fellowship.