Pituitary Adenoma Predisposition Caused by Germline Mutations in the
            <i>AIP</i>
            Gene

Vierimaa, Outi; Georgitsi, Marianthi; Lehtonen, Rainer; Vahteristo, Pia; Kokko, Antti; Raitila, Anniina; Tuppurainen, Karoliina; Ebeling, Tapani; Salmela, Pasi; Paschke, Ralf; Gündoğdu, Sadi; Menis, Ernesto De; Mäkinen, Markus J.; Launonen, Virpi; Karhu, Auli; Aaltonen, Lauri A.

doi:10.1126/science.1126100

Cited by 548 publications

(560 citation statements)

References 19 publications

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“…Recently, we reported that AIP is a low-penetrance tumour susceptibility gene, conferring genetic predisposition to pituitary adenomas with high relative, but low absolute, risk (Vierimaa et al, 2006). Little is known concerning the involvement of AIP in pituitary tumorigenesis or progression, as its functional role in that context remains to be clarified.…”

Section: Discussionmentioning

confidence: 99%

“…The coding region, exon-intron boundaries, as well as the 5 0 and 3 0 untranslated regions (UTRs) of AIP were PCR-amplified and sequenced as previously described by Vierimaa et al (2006). The potential splicing effect of an intronic change in one breast tumour sample was predicted by computational methods using NetGene2 (http://www.cbs.dtu.dk/services/NetGene2) and the Berkley Drosophila Genome Project (BDGP) (http://www.fruitfly.org/seq_tools/ splice.html) splice site prediction programs.…”

Section: Mutation Screeningmentioning

confidence: 99%

“…Germline mutations of aryl hydrocarbon receptor interacting protein (AIP), a gene coding for a cytoplasmic interaction partner of aryl hydrocarbon receptor (AHR) (also known as dioxin receptor), were recently described to cause low-penetrance pituitary adenoma predisposition (PAP) (Vierimaa et al, 2006).…”

mentioning

confidence: 99%

“…We recently described the PAP phenotype in pituitary adenoma patients from Northern Finland (Vierimaa et al, 2006). Germline AIP mutations segregated with the PAP phenotype in the familial cases, and germline mutations were also identified in sporadic acromegaly patients from Northern Finland.…”

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confidence: 99%

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Mutation analysis of aryl hydrocarbon receptor interacting protein (AIP) gene in colorectal, breast, and prostate cancers

et al. 2007

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Germline mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene were recently identified in individuals with pituitary adenoma predisposition (PAP). These patients have prolactin (PRL) or growth hormone (GH) oversecreting pituitary adenomas, the latter exhibiting acromegaly or gigantism. Loss-of-heterozygosity (LOH) analysis revealed that AIP is lost in PAP tumours, suggesting that it acts as a tumour-suppressor gene. Aryl hydrocarbon receptor interacting protein is involved in several pathways, but it is best characterised as a cytoplasmic partner of the aryl hydrocarbon receptor (AHR). To examine the possible role of AIP in the genesis of common cancers, we performed somatic mutation screening in a series of 373 colorectal cancers (CRCs), 82 breast cancers, and 44 prostate tumour samples. A missense R16H (47G4A) change was identified in two CRC samples, as well as in the respective normal tissues, but was absent in 209 healthy controls. The remaining findings were silent, previously unreported, changes of the coding, noncoding, or untranslated regions of AIP. These results suggest that somatic AIP mutations are not common in CRC, breast, and prostate cancers.

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Section: Discussionmentioning

confidence: 99%

Section: Mutation Screeningmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Mutation analysis of aryl hydrocarbon receptor interacting protein (AIP) gene in colorectal, breast, and prostate cancers

et al. 2007

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“…Recently, we showed that germ-line mutations of the aryl hydrocarbon receptor-interacting protein (AIP) gene cause pituitary adenoma predisposition (PAP) (8). A nonsense mutation, p.Q14X, was found in members of two Finnish families.…”

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confidence: 99%

Molecular diagnosis of pituitary adenoma predisposition caused by aryl hydrocarbon receptor-interacting protein gene mutations

Georgitsi

Raitila

Karhu

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Pituitary adenomas are common neoplasms of the anterior pituitary gland. Germ-line mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene cause pituitary adenoma predisposition (PAP), a recent discovery based on genetic studies in Northern Finland. In this population, a founder mutation explained a significant proportion of all acromegaly cases. Typically, PAP patients were of a young age at diagnosis but did not display a strong family history of pituitary adenomas. To evaluate the role of AIP in pituitary adenoma susceptibility in other populations and to gain insight into patient selection for molecular screening of the condition, we investigated the possible contribution of AIP mutations in pituitary tumorigenesis in patients from Europe and the United States. A total of 460 patients were investigated by AIP sequencing: young acromegaly patients, unselected acromegaly patients, unselected pituitary adenoma patients, and endocrine neoplasia-predisposition patients who were negative for MEN1 mutations. Nine AIP mutations were identified. Because many of the patients displayed no family history of pituitary adenomas, detection of the condition appears challenging. Feasibility of AIP immunohistochemistry (IHC) as a prescreening tool was tested in 50 adenomas: 12 AIP mutation-positive versus 38 mutation-negative pituitary tumors. AIP IHC staining levels proved to be a useful predictor of AIP status, with 75% sensitivity and 95% specificity for germ-line mutations. AIP contributes to PAP in all studied populations. AIP IHC, followed by genetic counseling and possible AIP mutation analysis in IHC-negative cases, a procedure similar to the diagnostics of the Lynch syndrome, appears feasible in identification of PAP.immunohistochemistry ͉ growth hormone/prolacting-secreting adenomas ͉ acromegaly

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The Molecular Genetics of Corticotroph Tumours

Dworakowska

Grossman

2014

Encyclopedia of Life Sciences

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Cushing disease caused by adrenocorticotropin ‐secreting pituitary adenomas leads to hypercortisolaemia predisposing to diabetes, hypertension, osteoporosis, central obesity, cardiovascular morbidity and increased mortality. Previous studies have enhanced our knowledge on the genetic basis of familial pituitary adenomas, including the McCune–Albright syndrome, multiple endocrine neoplasia types 1 and 2 (MEN1 and MEN2), Carney complex, the MEN1‐like phenotype (MEN4), pituitary adenoma predisposition syndromes and tuberous sclerosis. These studies, however, have done little to elucidate the causes of sporadic pituitary tumours, including Cushing disease. We summarise the information available on the molecular derangements of corticotroph tumours, including the most recent advances in the molecular genetics of sporadic lesions, which were published after the latest review on this topic written in 2011. We have left for further reading information about silent corticotroph adenomas, as well as plurihormonal expressing adenomas. We also suggest that more general literature for the readers who want to broaden their knowledge on the molecular biology in general of pituitary adrenomas. Key Concepts: Some 5% of pituitary adenomas are familial. Previous studies have enhanced our knowledge on the genetic basis of familial pituitary adenomas including the McCune–Albright syndrome (MAS), multiple endocrine neoplasia types 1 and 2 (MEN1 and MEN2), Carney complex (CNC), the MEN1‐like phenotype (MEN4), pituitary adenoma predisposition (PAP) syndromes and tuberous sclerosis (TSC). These studies, however, have done little to elucidate the causes of sporadic pituitary tumours, including Cushing disease. Molecular studies on pituitary tumours have shown that alterations in the best known tumour suppressor genes in other neoplasms (e.g. P53 , RB , etc.) or common oncogenes (e.g. the Ras ‐familly) are only rarely involved in the development of these tumours. Silent corticotroph adenomas (SCA) are rare pituitary tumours that are immunoreactive for ACTH, but without clinical evidence of Cushing disease, and tend to show aggressive features. Future work should focus on understanding the molecular mechanisms that control pituitary tumour transformation, where intracellular signalling molecules will constitute not only diagnostic/prognostic markers but also novel therapeutic targets.

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Pituitary Adenoma Predisposition Caused by Germline Mutations in the AIP Gene

Cited by 548 publications

References 19 publications

Mutation analysis of aryl hydrocarbon receptor interacting protein (AIP) gene in colorectal, breast, and prostate cancers

Mutation analysis of aryl hydrocarbon receptor interacting protein (AIP) gene in colorectal, breast, and prostate cancers

Molecular diagnosis of pituitary adenoma predisposition caused by aryl hydrocarbon receptor-interacting protein gene mutations

The Molecular Genetics of Corticotroph Tumours

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