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

Abstract

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

Genetic analysis in young patients with sporadic pituitary macroadenomas: besides AIP don't forget MEN1 genetic analysis

“…Bold represents the more likely at-risk haplotype shared by at least two subjects. near 7% (7,8). This prevalence reaches 14.3% in patients with GH-secreting tumors diagnosed before 25 years old (28).…”

“…In 2006, Vierimaa et al (4) identified mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene in the familial setting of PA. In FIPA kindreds, AIP mutations occur in 15-20% of cases (5), whereas they occur at a very low frequency in sporadic cases, between 0 and 4% (6,7,8,9). Because patients mutated for AIP (AIPmut) have typically early onset disease and larger PA compared with controls (10), Tichomirowa et al (11) performed AIP screening in young patients with isolated sporadic macroadenomas and identified that nearly 12% of patients had germline AIP mutations.…”

Decoding the genetic basis of Cushing's disease: USP8 in the spotlight

“…From a cohort of 74 pediatric patients with isolated CD, one presented with AIP and two with MEN1 mutations (14). Altogether, mutations in MEN1, AIP, CDKN1B or CDKN2C (encoding p18/INK4C) are rarely found in patients with CD (14,15,19,20). These features point to evidence against inheritance caused by germline mutations and suggest an acquired genetic basis of CD.…”

The clinical, pathological, and genetic features of familial isolated pituitary adenomas

“…This suggests that amino acid substitutions, such as R16H for instance, could be expected to have functional significance. Indeed, since we reported germline R16H changes in a FIPA family, others have noted similar mutations in four sporadic pituitary adenoma patients and also in the germline and tumors of two patients with colorectal carcinoma (and family histories of colorectal, carcinoid, and other tumors) (47,48). A full appreciation of the effect of R16H on AIP expression and/or function will be required to determine whether this is Familial isolated pituitary adenomas truly a pathogenic mutation.…”

“…With the identification of AIP mutations as being involved in the etiology of familial pituitary tumors, the issue of screening has been raised (47). In particular, it has been suggested that immunohistochemistry for AIP in pituitary tumor tissue be used to screen operated patients for mutations.…”