The aryl hydrocarbon receptor interacting protein (AIP) is a tumor-suppressor gene underlying the pituitary adenoma predisposition. Thus far, the exact molecular mechanisms by which inactivated AIP exerts its tumor-promoting action have been unclear. To better understand the role of AIP in pituitary tumorigenesis, we performed gene expression microarray analysis to examine changes between Aip wild-type and knockout mouse embryonic fibroblast (MEF) cell lines. Transcriptional analyses implied that Aip deficiency causes a dysfunction in cyclic adenosine monophosphate (cAMP) signaling, as well as impairments in signaling cascades associated with developmental and immune-inflammatory responses. In vitro experiments showed that AIP deficiency increases intracellular cAMP concentrations in both MEF and murine pituitary adenoma cell lines. Based on knockdown of various G protein α subunits, we concluded that AIP deficiency leads to elevated cAMP concentrations through defective Gαi-2 and Gαi-3 proteins that normally inhibit cAMP synthesis. Furthermore, immunostaining of Gαi-2 revealed that AIP deficiency is associated with a clear reduction in Gαi-2 protein expression levels in human and mouse growth hormone (GH)-secreting pituitary adenomas, thus indicating defective Gαi signaling in these tumors. By contrast, all prolactin-secreting tumors showed prominent Gαi-2 protein levels, irrespective of Aip mutation status. We additionally observed reduced expression of phosphorylated extracellular signal-regulated kinases 1/2 and cAMP response element-binding protein levels in mouse and human AIP-deficient somatotropinomas. This study implies for the first time that a failure to inhibit cAMP synthesis through dysfunctional Gαi signaling underlies the development of GH-secreting pituitary adenomas in AIP mutation carriers.

Mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene have been shown to predispose to pituitary adenoma predisposition, a condition characterized by growth hormone (GH)-secreting pituitary tumors. To study AIP-mediated tumorigenesis, we generated an Aip mouse model. Heterozygous mice developed normally but were prone to pituitary adenomas, in particular to those secreting GH. A complete loss of AIP was detected in these lesions, and full penetrance was reached at the age of 15 months. No excess of any other tumor type was found. Ki-67 analysis indicated that Aip-deficient tumors have higher proliferation rates compared with Aip-proficient tumors, suggesting a more aggressive disease. Similar to human AIP-deficient pituitary adenomas, immunohistochemical studies showed that expression of aryl hydrocarbon receptor nuclear translocator 1 or 2 (ARNT or ARNT2) protein was lost in the mouse tumors, suggesting that mechanisms of AIP-related tumorigenesis involve aberrant ARNT function. The Aip ؉/؊ mouse appears to be an excellent model for the respective human disease phenotype. This model constitutes a tool to further study AIPassociated pituitary tumorigenesis and may be potentially valuable in efforts to develop therapeutic strategies to treat pituitary adenomas. Pituitary adenomas are common, benign, monoclonal neoplasms of the anterior pituitary gland. They account for approximately 15% of intracranial tumors. Approximately two thirds produce pituitary hormones in excess; among these, prolactin (PRL) and growth hormone (GH)-oversecreting adenomas are the most common. The significant morbidity associated with these lesions arises from the adverse effects of the hypersecretion, such as acromegaly or gigantism in the case of GH secreting adenomas, and/or local compressive effects. 1Mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene have been identified as an underlying cause in human pituitary adenoma predisposition (OMIM 102200), characterized mainly by GH secreting adenomas (somatotropinomas), although susceptibility to PRL (prolactinomas), adrenocorticotropic hormone (ACTH), and nonsecreting adenomas is also part of the disease phenotype. [2][3][4][5] So far AIP mutations have not been associated with any other tumor types.6 -8 Typically, pituitary adenoma predisposition patients have a young age at disease onset but do not necessarily display a strong family history of pituitary adenomas. AIP mutation positive tumors seem to be larger and may have a worse response to somatostatin analogs as compared to sporadic tumors. 4,5,9 Inactivating germline mutations, loss of the normal allele in tumors, as well as recent functional evidence implicate the tumor suppressor role of the AIP gene. 2,5,10 Many of the proteins known to interact with AIP can be linked to tumorigenesis. The best known function of AIP is to stabilize aryl hydrocarbon receptor (AHR) (also known The American Journal of Pathology, Vol. 177, No. 4, October 2010 Copyright © American Society for Investigative P...

It is estimated that up to 35% of colorectal cancers (CRC) can be explained by hereditary factors. However, genes predisposing to highly penetrant CRC syndromes account for only a small fraction of all cases. Thus, most CRCs still remain molecularly unexplained. A recent systematic sequencing study on well-annotated human protein coding genes identified 280 somatically mutated candidate cancer genes (CAN genes) in breast and colorectal cancer. It is estimated that 8% of all reported cancer genes show both somatic and germline mutations. Therefore, the identified CAN genes serve as a distinct set of candidates for being involved in hereditary susceptibility. The aim of this study was to evaluate the role of colorectal CAN genes in familial CRC. Samples from 45 familial CRCs without known cancer predisposing mutations were screened for somatic and germline variants in 15 top-ranked CAN genes. Six of the genes were found to be somatically mutated in our tumor series. We identified 22 nonsynonymous somatic mutations of which the majority was of missense type. In germline, three novel nonsynonymous variants were identified in the following genes: CSMD3, EPHB6 and C10orf137, and none of the variants were present in 890 population-matched healthy controls. It is possible that the identified germline variants modulate predisposition to CRC. Functional validation and larger sample sets, however, will be required to clarify the role of the identified germline variants in CRC susceptibility.

Pituitary adenomas are common in the general population. Although most of them are sporadic, some occur in a familial setting. In familial pituitary adenoma patients it is common that no germline defects are found after screening of aryl hydrocarbon receptor interacting protein (AIP ) and other genes known to underlie the condition, suggesting the existence of yet unknown predisposition genes. Recently, the RET proto-oncogene was found to be a novel in vivo interaction partner of AIP in the pituitary gland. Here, we have screened patients from 16 AIP mutation negative (AIPmutK) pituitary adenoma families for RET germline mutations to assess whether RET could play a role in pituitary adenoma predisposition, similar to AIP. We found five novel germline RET changes: one in RET Exon 4 and the rest in noncoding regions of RET. Two changes, c.1560*GOA and K1285GOA, were segregated in affected family members. We also analyzed the RET region with enhancer element locator (EEL) to identify RET regulatory elements, and to see whether the changes resided in these. None of the variants mapped to the regions predicted by EEL. Expression of RET was examined in ten AIPmutK and seven AIP mutation positive (AIPmutC) somatotropinomas by immunohistochemistry, with a trend showing reduced expression in the latter (PZ0 . 05). We conclude that the RET variants are presumably not related to pituitary adenoma predisposition, although reduced RET expression may play a role in AIP-related genesis of somatotropinomas.

When all costs are considered from an inpatient setting, LUTONIX® 035 DCB is predicted to result in total cost-savings compared with PTA. Sensitivity analyses demonstrate consistent results across a range of scenarios and a potential for cost savings from inpatient settings. ConClusions: The economic analysis predicted LUTONIX® 035 DCB may be cost-effective. The cost per reintervention avoided for LUTONIX® 035 DCB is comparable to other published studies of cost-effective DCBs.