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...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier España
2010-01-01
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| Series: | Clinics |
| Subjects: | |
| Online Access: | http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1807-59322010000400010 |
| _version_ | 1811228625341513728 |
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| author | Rodrigo A. Toledo 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 |
| author_facet | Rodrigo A. Toledo 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 |
| author_sort | Rodrigo A. Toledo |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-12T10:00:15Z |
| format | Article |
| id | doaj.art-bd3acfd134e94c3fb447bd7d6ce60425 |
| institution | Directory Open Access Journal |
| issn | 1807-5932 1980-5322 |
| language | English |
| last_indexed | 2024-04-12T10:00:15Z |
| publishDate | 2010-01-01 |
| publisher | Elsevier España |
| record_format | Article |
| series | Clinics |
| spelling | doaj.art-bd3acfd134e94c3fb447bd7d6ce604252022-12-22T03:37:35ZengElsevier EspañaClinics1807-59321980-53222010-01-0165440741510.1590/S1807-59322010000400010Isolated familial somatotropinoma: 11Q13-LOH and gene/protein expression analysis suggests a possible involvement of aip also in non-pituitary tumorigenesisRodrigo A. ToledoBerenice B. MendoncaMaria Candida B. V. FragosoIberê C. SoaresMadson Q. AlmeidaMichelle B. MoraesDelmar M. Lourenço-JrVenâncio A. F. AlvesMarcello D. BronsteinSergio P. A. ToledoOBJECTIVE: 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.http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1807-59322010000400010Acromegalypituitary tumorFIPAAIPAdrenocortical tumor |
| spellingShingle | Rodrigo A. Toledo 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 Isolated familial somatotropinoma: 11Q13-LOH and gene/protein expression analysis suggests a possible involvement of aip also in non-pituitary tumorigenesis Clinics Acromegaly pituitary tumor FIPA AIP Adrenocortical tumor |
| 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 | Acromegaly pituitary tumor FIPA AIP Adrenocortical tumor |
| url | http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1807-59322010000400010 |
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