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

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 examine...

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Autores principales: Toledo, Rodrigo A., Mendonca, Berenice B., Fragoso, Maria Candida B. V., Soares, Iberê C., Almeida, Madson Q., Moraes, Michelle B., Lourenço, Delmar M., Alves, Venâncio A. F., Bronstein, Marcello D., Toledo, Sergio P. A.
Formato: Texto
Lenguaje:English
Publicado: Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2862671/
https://www.ncbi.nlm.nih.gov/pubmed/20454499
http://dx.doi.org/10.1590/S1807-59322010000400010
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author Toledo, Rodrigo A.
Mendonca, Berenice B.
Fragoso, Maria Candida B. V.
Soares, Iberê C.
Almeida, Madson Q.
Moraes, Michelle B.
Lourenço, Delmar M.
Alves, Venâncio A. F.
Bronstein, Marcello D.
Toledo, Sergio P. A.
author_facet Toledo, Rodrigo A.
Mendonca, Berenice B.
Fragoso, Maria Candida B. V.
Soares, Iberê C.
Almeida, Madson Q.
Moraes, Michelle B.
Lourenço, Delmar M.
Alves, Venâncio A. F.
Bronstein, Marcello D.
Toledo, Sergio P. A.
author_sort Toledo, Rodrigo A.
collection PubMed
description 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.
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spelling pubmed-28626712010-05-07 Isolated familial somatotropinoma: 11q13-loh and gene/protein expression analysis suggests a possible involvement of aip also in non-pituitary tumorigenesis Toledo, Rodrigo A. Mendonca, Berenice B. Fragoso, Maria Candida B. V. Soares, Iberê C. Almeida, Madson Q. Moraes, Michelle B. Lourenço, Delmar M. Alves, Venâncio A. F. Bronstein, Marcello D. Toledo, Sergio P. A. Clinics (Sao Paulo) Clinical Sciences 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. Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo 2010-04 /pmc/articles/PMC2862671/ /pubmed/20454499 http://dx.doi.org/10.1590/S1807-59322010000400010 Text en Copyright © 2010 Hospital das Clínicas da FMUSP http://creativecommons.org/licenses/by-nc/3.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Clinical Sciences
Toledo, Rodrigo A.
Mendonca, Berenice B.
Fragoso, Maria Candida B. V.
Soares, Iberê C.
Almeida, Madson Q.
Moraes, Michelle B.
Lourenço, Delmar M.
Alves, Venâncio A. F.
Bronstein, Marcello D.
Toledo, Sergio P. A.
Isolated familial somatotropinoma: 11q13-loh and gene/protein expression analysis suggests a possible involvement of aip also in non-pituitary tumorigenesis
title Isolated familial somatotropinoma: 11q13-loh and gene/protein expression analysis suggests a possible involvement of aip also in non-pituitary tumorigenesis
title_full Isolated familial somatotropinoma: 11q13-loh and gene/protein expression analysis suggests a possible involvement of aip also in non-pituitary tumorigenesis
title_fullStr Isolated familial somatotropinoma: 11q13-loh and gene/protein expression analysis suggests a possible involvement of aip also in non-pituitary tumorigenesis
title_full_unstemmed Isolated familial somatotropinoma: 11q13-loh and gene/protein expression analysis suggests a possible involvement of aip also in non-pituitary tumorigenesis
title_short Isolated familial somatotropinoma: 11q13-loh and gene/protein expression analysis suggests a possible involvement of aip also in non-pituitary tumorigenesis
title_sort isolated familial somatotropinoma: 11q13-loh and gene/protein expression analysis suggests a possible involvement of aip also in non-pituitary tumorigenesis
topic Clinical Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2862671/
https://www.ncbi.nlm.nih.gov/pubmed/20454499
http://dx.doi.org/10.1590/S1807-59322010000400010
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