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Case Reports
. 2010 Apr;65(4):407-15.
doi: 10.1590/S1807-59322010000400010.

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

Rodrigo A Toledo  1 , Berenice B Mendonca, Maria Candida B V Fragoso, Iberê C Soares, Madson Q Almeida, Michelle B Moraes, Delmar M Lourenço Jr, Venâncio A F Alves, Marcello D Bronstein, Sergio P A Toledo
Affiliations
Case Reports

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

Rodrigo A Toledo et al. Clinics (Sao Paulo). 2010 Apr.

Abstract

Objective: Non-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.

Patients: We 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.

Design: Mutational 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.

Results: The 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.

Conclusions: Our 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.

Keywords: AIP; Acromegaly; Adrenocortical tumor; FIPA; pituitary tumor.

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Figures

Figure 1
Figure 1
Genealogy: identification of a functional AIP mutation that may disrupt the cAMP signaling pathway. A - The index patient developed acromegaly, adrenocortical carcinoma and B-cell lymphoma. One of her daughters had acromegaly due to a large and invasive somatotropinoma. B - The known AIP functional mutation c.241C>T (R81X) was identified in genomic DNA samples from both patients (mother and daughter) with acromegaly but not in the three unaffected family members.
Figure 2
Figure 2
Loss of AIP in the familial somatotropinoma. A - The MRI of the index patient’s daughter revealed a large and invasive pituitary adenoma (so-matotropinoma) that was resistant to treatment with a somatostatin analog. She inherited the heterozygous R81X AIP germline mutation (Fig. 1B) from the index case. B - The sequence analysis of AIP in tumoral DNA samples revealed that only the R81X-mutated allele (t) was present in the somatotropinoma, indicating somatic loss and inactivation of wild-type AIP. C - The immunohistochemical analysis showed AIP protein expression in the normal pituitary and a GH-secreting pituitary adenoma of a patient with sporadic acromegaly without AIP mutation. The somatotropinoma of the patient harboring the R81X germline mutation and the somatic loss of the gene presented low AIP protein expression.
Figure 3
Figure 3
Loss of AIP in the adrenocortical tumor. A - An abdominal imaging scan of the index case when she presented with virilization and high serum levels of adrenal steroids. The scan revealed a large heterogeneous mass (9.0 cm x 8.9 cm) in the right adrenal gland, which was surgically excised and histopathologically classified as adrenocortical carcinoma. B - Sequence and microsatellite (D11S1258 AIP-flanking marker) analyses of DNA samples from the tumor revealed loss of the wild-type AIP allele. C - The 2-δ δ CT method was used to compare AIP mRNA expression in pooled normal pituitary glands (Ct AIP=25.66, Ct β-actin=24.24), pooled normal adrenal glands (Ct AIP=25.42; Ct β-actin=22.49) and the adrenocortical carcinoma from the index case, in whom the AIP wild-type allele was lost (Ct AIP=31.53, Ct β-actin=27.28). The mean Ct value of the normal adrenal pool was used as a reference (1.0), by comparison, there was decreased AIP expression in the adrenocortical carcinoma (0.48). D - Immunohistochemistry using the AIP antibody showed low/ moderate staining in a normal adrenal gland obtained from autopsy. A complete loss of AIP immunoreactivity was observed in the adrenocortical carcinoma from the index patient, which stained positive for Melan A and 35betaH11, which were used as positive controls.
Figure 4
Figure 4
Maintenance of heterozygosity and positive AIP immunostaining in the B-cell non-Hodgkin lymphoma of the R81X AIP mutated IFS patient.
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