Isolated familial somatotropinoma: 11q13-loh and gene/protein expression analysis suggests a possible involvement of aip also in non-pituitary tumorigenesis

Abstract

OBJECTIVENon-pituitary tumors have been reported in a subset of patients harboring germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene. However, no detailed investigations of non-pituitary tumors of AIP-mutated patients have been reported so far.PATIENTSWe examined a MEN1- and p53-negative mother-daughter pair with acromegaly due to somatotropinoma. Subsequently, the mother developed a large virilizing adrenocortical carcinoma and a grade II B-cell non-Hodgkin’s lymphoma.DESIGNMutational analysis was performed by automated sequencing. Loss-of-heterozygosity (LOH) analysis was carried out by sequencing and microsatellite analysis. AIP expression was assessed through quantitative PCR (qPCR) and immunohistochemistry.RESULTSThe functional inactivating mutation c.241C>T (R81X), which blocks the AIP protein from interacting with phosphodiesterase 4A (PDE4A), was identified in the heterozygous state in the leukocyte DNA of both patients. Analyzing the tumoral DNA revealed that the AIP wild-type allele was lost in the daughter’s somatotropinoma and the mother’s adrenocortical carcinoma. Both tumors displayed low AIP protein expression levels. Low AIP gene expression was confirmed by qPCR in the adrenocortical carcinoma. No evidence of LOH was observed in the DNA sample from the mother’s B-cell lymphoma, and this tumor displayed normal AIP immunostaining.CONCLUSIONSOur study presents the first molecular analysis of non-pituitary tumors in AIP-mutated patients. The finding of AIP inactivation in the adrenocortical tumor suggests that further investigation of the potential role of this recently identified tumor suppressor gene in non-pituitary tumors, mainly in those tumors in which the cAMP and the 11q13 locus are implicated, is likely to be worthwhile.

The p.R16H (C.47G>A) AIP gene variant in a case with invasive non-functioning pituitary macroadenoma and Screening of a Control Cohort

“…Other tumors observed in PA patients include one LOH-negative meningioma in a p.R81X positive somatotropinoma patient (29) and a malignant melanoma (LOH unknown) in a p.R16H German NFPA patient (30). In a patient from an AIP p.R81X isolated somatotropinoma family two tumors were tested for LOH and AIP mRNA and protein expression: an adrenal carcinoma, which presented LOH and was AIP-deficient and a B cell lymphoma, LOH negative and with normal AIP expression, suggesting selective involvement of AIP in these tumors (31).…”

p27 variant and corticotropinoma susceptibility: a genetic and in vitro study

“…The diagnosis of endocrine tumors was performed by standardized clinical, biochemical, and imaging examinations (Toledo et al 2009, 2010a, Lourenco et al 2010. Other possible endocrine tumors were ruled out in each patient.…”

“…TMEM127 and RET mutations were ruled out in the 51 cases with pheochromocytomas as previously described (Yao et al 2010). The previously described cases from our MEN1 cohort (Toledo et al 2010a) were not included in this study.…”

The Role of Aryl Hydrocarbon Receptor (AHR) and AHR-Interacting Protein (AIP) in the Pathogenesis of Pituitary Adenomas

“…In addition, inherited predisposition linked to the AIP gene is characterized by an incomplete or low penetrance, which strongly supports the need for additional factors to initiate or promote pituitary tumorigenesis and stimulates research work aimed to their identi fi cation. Another open issue remains the pituitary speci fi city of AIP -related neoplasia, since additional tumors have been occasionally observed in AIP mut patients, and LOH in 11q13 with loss of the wild-type AIP allele was recently reported by Toledo et al ( 2010 ) in an adrenocortical carcinoma operated on in an acromegalic patient with a truncating familial AIP mutation. Because AIP has a rather ubiquitous expression, the signalling pathways which are potentially disrupted by AIP mutations may be relevant for tumorigenesis in other tissues.…”