Aryl Hydrocarbon Receptor-interacting Protein Mutations Research Articles

No evidence of somatic aryl hydrocarbon receptor interacting protein mutations in sporadic endocrine neoplasia

Germline mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene were recently observed in patients with pituitary adenoma predisposition (PAP). Though AIP mutation-positive individuals with prolactin-, mixed growth hormone/prolactin-, and ACTH-producing pituitary adenomas as well as non-secreting pituitary adenomas have been reported, most mutation-positive patients have had growth hormone-producing adenomas diagnosed at relatively young age. Pituitary adenomas are also component tumors of some familial endocrine neoplasia syndromes such as multiple endocrine neoplasia type 1 (MEN1) and Carney complex (CNC). Genes underlying MEN1 and CNC are rarely mutated in sporadic pituitary adenomas, but more often in other lesions contributing to these two syndromes. Thus far, the occurrence of somatic AIP mutations has not been studied in endocrine tumors other than pituitary adenomas. Here, we have analyzed 32 pituitary adenomas and 79 other tumors of the endocrine system for somatic AIP mutations by direct sequencing. No somatic mutations were identified. However, two out of nine patients with prolactin-producing adenoma were shown to harbor a Finnish founder mutation (Q14X) with a complete loss of the wild-type allele in the tumors. These results are in agreement with previous studies in that prolactin-producing adenomas are component tumors in PAP. The data also support the previous finding that somatic AIP mutations are not common in pituitary adenomas and suggest that such mutations are rare in other endocrine tumors as well.

AIP gene in pituitary adenoma predisposition

Germline mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene were recently shown to cause susceptibility to pituitary adenoma predisposition. The purpose of this review is to briefly recapitulate the current knowledge on hereditary susceptibility to pituitary adenomas and what led to the identification of AIP as a novel predisposition gene. We will then concentrate on the data on AIP mutations and pituitary adenoma predisposition phenotype that have accumulated since the gene was identified. Major future challenges, as well as the possibilities for clinical practice based on this recent finding, will also be discussed.

AIP Mutations are not Identified in Patients with Sporadic Pituitary Adenomas

The pathogenesis of pituitary adenomas remains a subject of interest. Recently, mutations in the aryl hydrocarbon receptor-interacting protein (AIP) were identified as germline events leading to pituitary tumor predisposition in Finnish and Italian families with familial growth hormone-secreting pituitary adenomas and acromegaly. We examined the frequency of AIP mutations in pituitary tumors and blood of Canadian patients with sporadic pituitary somatotroph adenomas and sporadic pituitary adenomas of other types. Genomic DNA was extracted from pituitary tumors and white blood cells obtained from peripheral blood. Three PCR reactions were carried out to amplify the sites of known mutation, and amplified products were sequenced. AIP mutations were not detected as germline events in blood or as somatic alterations in tumors of 66 patients with pituitary adenomas. These included 50 acromegalics and 16 patients with other types of pituitary tumor. No mutations were detected in the blood of 22 controls and 10 patients with other endocrinopathies. Our results indicate that mutations in AIP are not identified in sporadic pituitary adenomas of Canadian patients. This rare mechanism of pituitary tumorigenesis appears to be unique to the initial Finnish and Italian families described.

Mutations in theAryl Hydrocarbon Receptor Interacting ProteinGene Are Not Highly Prevalent among Subjects with Sporadic Pituitary Adenomas

Limited screening suggests that three germline mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene are not involved in sporadic pituitary tumorigenesis. Multiple novel mutations of this gene have since been identified in familial isolated pituitary adenoma cohorts. The objective of the study was to undertake full AIP coding sequence screening to assess for the presence of germline and somatic mutations in European Union subjects with sporadic pituitary tumors. The study design was the analysis of DNA from peripheral blood lymphocytes and analysis of exons 1-6 and paraexonic intron sequences of AIP. Multiplex ligation-dependent probe amplification was used to screen separate sporadic pituitary tumor tissue samples for discrete and extensive deletions or mutations of the AIP gene. The study was conducted in university tertiary referral Clinical Genetics, Molecular Biology, and Endocrinology Departments. In 107 patients [prolactinomas (n =49), nonfunctioning tumors (n = 29), somatotropinomas (n = 26), ACTH-secreting tumors (n = 2), TSH-secreting tumors (n = 1)], no germline mutations of AIP were demonstrated. Among a group of 41 tumor samples from other subjects, a novel AIP mutation (R22X) was found in one sample in which the corresponding allele was deleted; follow-up screening of the patient demonstrated a germline R22X AIP mutation. AIP mutations do not appear to play a prominent role in sporadic pituitary tumorigenesis in this population of European subjects.

Aryl Hydrocarbon Receptor-Interacting Protein Gene Mutations in Familial Isolated Pituitary Adenomas: Analysis in 73 Families

An association between germline aryl hydrocarbon receptor-interacting protein (AIP) gene mutations and pituitary adenomas was recently shown. The objective of the study was to assess the frequency of AIP gene mutations in a large cohort of patients with familial isolated pituitary adenoma (FIPA). This was a multicenter, international, collaborative study. The study was conducted in 34 university endocrinology and genetics departments in nine countries. Affected members from each FIPA family were studied. Relatives of patients with AIP mutations underwent AIP sequence analysis. Presence/absence and description of AIP gene mutations were the main outcome measures. There was no intervention. Seventy-three FIPA families were identified, with 156 patients with pituitary adenomas; the FIPA cohort was evenly divided between families with homogeneous and heterogeneous tumor expression. Eleven FIPA families had 10 germline AIP mutations. Nine mutations, R16H, G47_R54del, Q142X, E174frameshift, Q217X, Q239X, K241E, R271W, and Q285frameshift, have not been described previously. Tumors were significantly larger (P = 0.0005) and diagnosed at a younger age (P = 0.0006) in AIP mutation-positive vs. mutation-negative subjects. Somatotropinomas predominated among FIPA families with AIP mutations, but mixed GH/prolactin-secreting tumors, prolactinomas, and nonsecreting adenomas were also noted. Approximately 85% of the FIPA cohort and 50% of those with familial somatotropinomas were negative for AIP mutations. AIP mutations, of which nine new mutations have been described here, occur in approximately 15% of FIPA families. Although pituitary tumors occurring in association with AIP mutations are predominantly somatotropinomas, other tumor types are also seen. Further study of the impact of AIP mutations on protein expression and activity is necessary to elucidate their role in pituitary tumorigenesis in FIPA.

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

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 (47G>A) 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, non-coding, or untranslated regions of AIP. These results suggest that somatic AIP mutations are not common in CRC, breast, and prostate cancers.