title: Isolated familial somatotropinoma: 11q13-loh and gene/protein expression analysis suggests a possible involvement of aip also in non-pituitary tumorigenesis.
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.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
authors.affiliation: Unidade de Endocrinologia Genética, LIM/25, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil. toledorodrigo@usp.br
authors.forename: Rodrigo A
authors.initials: RA
authors.lastname: Toledo
authors.forename: Berenice B
authors.initials: BB
authors.lastname: Mendonca
authors.forename: Maria Candida B V
authors.initials: MC
authors.lastname: Fragoso
authors.forename: Iberê C
authors.initials: IC
authors.lastname: Soares
authors.forename: Madson Q
authors.initials: MQ
authors.lastname: Almeida
authors.forename: Michelle B
authors.initials: MB
authors.lastname: Moraes
authors.forename: Delmar M
authors.initials: DM
authors.lastname: Lourenço
authors.forename: Venâncio A F
authors.initials: VA
authors.lastname: Alves
authors.forename: Marcello D
authors.initials: MD
authors.lastname: Bronstein
authors.forename: Sergio P A
authors.initials: SP
authors.lastname: Toledo
mesh_terms: D000172:Acromegaly / Q000235:genetics*; D000236:Adenoma / Q000235:genetics* / Q000378:metabolism; D000293:Adolescent; D018268:Adrenocortical Carcinoma / Q000235:genetics*; D000328:Adult; D005260:Female; D015870:Gene Expression; D016158:Genes, p53; D018095:Germ-Line Mutation; D049912:Growth Hormone-Secreting Pituitary Adenoma / Q000235:genetics*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D019656:Loss of Heterozygosity / Q000235:genetics; D018761:Multiple Endocrine Neoplasia Type 1 / Q000235:genetics; D010911:Pituitary Neoplasms / Q000235:genetics* / Q000378:metabolism; D016133:Polymerase Chain Reaction
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C103265:aryl hydrocarbon receptor-interacting protein
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