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Koen M A Dreijerink, H T Marc Timmers, and Myles Brown

Since the discovery of the multiple endocrine neoplasia type 1 (MEN1) gene in 1997, elucidation of the molecular function of its protein product, menin, has been a challenge. Biochemical, proteomics, genetics and genomics approaches have identified various potential roles, which converge on gene expression regulation. The most consistent findings show that menin connects transcription factors and chromatin-modifying enzymes, in particular, the histone H3K4 methyltransferase complexes MLL1 and MLL2. Chromatin immunoprecipitation combined with next-generation sequencing has enabled studying genome-wide dynamics of chromatin binding by menin. We propose that menin regulates cell type-specific transcriptional programs by linking chromatin regulatory complexes to specific transcription factors. In this fashion, the MEN1 gene is a tumor suppressor gene in the endocrine tissues that are affected in MEN1. Recent studies have hinted at possibilities to pharmacologically restore the epigenetic changes caused by loss of menin function as therapeutic strategies for MEN1, for example, by inhibition of histone demethylases. The current lack of appropriate cellular model systems for MEN1-associated tumors is a limitation for compound testing, which needs to be addressed in the near future. In this review, we look back at the past twenty years of research on menin and the mechanism of disease of MEN1. In addition, we discuss how the current understanding of the molecular function of menin offers future directions to develop novel treatments for MEN1-associated endocrine tumors.

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Frederieke M Brouwers, Sven Gläsker, Amanda F Nave, Alexander O Vortmeyer, Irina Lubensky, Steven Huang, Mones S Abu-Asab, Graeme Eisenhofer, Robert J Weil, Deric M Park, W Marston Linehan, Karel Pacak, and Zhengping Zhuang

Pheochromocytomas are catecholamine-producing tumors that can occur in the context of von Hippel–Lindau syndrome (VHL) and multiple endocrine neoplasia type 2 (MEN2). Pheochromocytomas in these two syndromes differ in histopathological features, catecholamine metabolism, and clinical phenotype. To further investigate the nature of these differences, we compared the global protein expressions of 8 MEN2A-associated pheochromocytomas with 11 VHL-associated pheochromocytomas by two-dimensional gel electrophoresis proteomic profiling followed by sequencing and identification of differentially expressed proteins. Although both types of pheochromocytoma shared similarities in their protein expression patterns, the expression of several proteins was distinctly different between VHL- and MEN2A-associated pheochromocytomas. We identified several of these differentially expressed proteins. One of the proteins with higher expression in MEN2-associated tumors was chromogranin B, of which the differential expression was confirmed by western blot analysis. Our results expand the evidence for proteomic differences between these two tumor entities, and suggest that VHL-associated pheochromocytomas may be deficient in fundamental machinery for catecholamine storage. In light of these new findings, as well as existing evidence for differences between both types of pheochromocytomas, we propose that these tumors may have different developmental origins.

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Francien H van Nederveen, Esther Korpershoek, Ronald J deLeeuw, Albert A Verhofstad, Jacques W Lenders, Winand N M Dinjens, Wan L Lam, and Ronald R de Krijger

Pheochromocytomas (PCC) are catecholamine-producing tumors arising from the adrenal medulla that occur either sporadically or in the context of hereditary cancer syndromes, such as multiple endocrine neoplasia type 2 (MEN2), von Hippel-Lindau disease (VHL), neurofibromatosis type 1, and the PCC-paraganglioma syndrome. Conventional comparative genomic hybridization studies have shown loss of 1p and 3q in the majority of sporadic and MEN2-related PCC, and 3p and 11p loss in VHL-related PCC. The development of a submegabase tiling resolution array enabled us to perform a genome-wide high-resolution analysis of 36 sporadic benign PCC. The results show that there are two distinct patterns of abnormalities in these sporadic PCC, one consisting of loss of 1p with or without concomitant 3q loss in 20/36 cases (56%), the other characterized by loss of 3p with or without concomitant 11p loss in 11/36 (31%). In addition, we found loss of chromosome 22q at high frequency (35%), as well as the novel finding of high frequency chromosome 21q loss (21%). We conclude that there appear to be two subgroups of benign sporadic PCC, one of which has a pattern of chromosomal abnormalities that is comparable with PCC from patients with MEN2 and the other that is comparable with the PCC that arise in patients with VHL disease. In addition, genes on 21q and 22q might play a more important role in PCC pathogenesis than had been assumed thus far.

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Xiao-Hua Jiang, Jie-Li Lu, Bin Cui, Yong-Ju Zhao, Wei-qing Wang, Jian-Min Liu, Wen-Qiang Fang, Ya-Nan Cao, Yan Ge, Chang-xian Zhang, Huguette Casse, Xiao-Ying Li, and Guang Ning

Multiple endocrine neoplasia type 1 (MEN1) is an inherited tumour syndrome characterized by the development of tumours of the parathyroid, anterior pituitary and pancreatic islets, etc. Heterozygous germ line mutations of MEN1 gene are responsible for the onset of MEN1. We investigated the probands and 31 family members from eight unrelated Chinese families associated with MEN1 and identified four novel mutations, namely 373_374ins18, 822delT, 259delT and 1092delC, as well as three previously reported mutations, such as 357_360delCTGT, 427_428delTA and R108X (CGA>TGA) of MEN1 gene. Furthermore, we detected a loss of heterozygosity (LOH) at chromosome 11q in the removed tumours, including gastrinoma, insulinoma and parathyroid adenoma from two probands of MEN1 families. RT-PCR and direct sequencing showed that mutant MEN1 transcripts remained in the MEN1-associated endocrine tumours, whereas normal menin proteins could not be detected in those tumours by either immunohistochemistry or immunoblotting. In conclusion, MEN1 heterozygous mutations are associated with LOH and menin absence, which are present in MEN1-associated endocrine tumours.

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F W F Hanna, R T Cunningham, J E S Ardill, C F Johnston, C F J Russell, and K D Buchanan

A good prognosis in medullary thyroid carcinoma (MTC) has been correlated with homogenous immunohistochemical staining using antibodies to calcitonin (CT). Also, for unexplained reasons, multiple endocrine neoplasia (MEN) 2A and sporadic MTC patients had a better prognosis than MEN 2B patients. However, the post-operative serum CT level was not helpful in predicting the prognosis.

The aim of this work was to reassess the prognostic factors in MTC, employing these three parameters in 16 patients (6 MEN 2A and 10 sporadic) for a period of more than 15 years.

Normalization of post-tumour resection serum CT was associated with significant improvement of survival (P=0.0009) and in the quality of life (P=0.0002). In accordance with previous reports, MEN 2A patients had a better prognosis than sporadic patients. The pattern of immunohistochemical staining was not helpful in assessing prognosis.

We conclude that normalization of post-operative serum CT is a helpful and practical tool in assessing the prognosis in MTC patients.

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M Theodoropoulou, I Cavallari, L Barzon, D M D'Agostino, T Ferro, T Arzberger, Y Grübler, L Schaaf, M Losa, F Fallo, V Ciminale, G K Stalla, and U Pagotto

Pituitary adenomas represent one of the key features of multiple endocrine neoplasia type 1. The gene involved in this syndrome (MEN1) is a putative tumor suppressor, that codes for a 610-amino acid nuclear protein termed 'menin'. Analyses of sporadic pituitary adenomas have so far failed to reveal MEN1 mutations or defects in MEN1 transcription in these tumors. In the present study we detected menin protein expression in a panel of normal and tumoral pituitary tissues, using a monoclonal antibody against the carboxy-terminus of menin. In the normal human pituitary gland, strong nuclear staining for menin was detectable in the majority of the endocrine cells of the anterior lobe, without a clear association with a particular hormone-producing type. In sporadic pituitary adenomas, menin expression was variable, with a high percentage of cases demonstrating a significant decrease in menin immunoreactivity when compared with the normal pituitary. Interestingly, metastatic tissues derived from one pituitary carcinoma had no detectable menin levels. Altogether, our data provide the first information regarding the status of menin expression in human normal and neoplastic pituitary as determined by immunohistochemistry (IHC).

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Xinyu Wu, Shiaoching Gong, Pradip Roy-Burman, Peng Lee, and Zoran Culig

Mouse models of prostate cancer (PCa) are critical for understanding the biology of PCa initiation, progression, and treatment modalities. Here, we summarize recent advances in PCa mouse models that led to new insights into specific gene functions in PCa. For example, the study of transgenic mice with TMPRSS2/ERG, an androgen-regulated fusion protein, revealed its role in developing PCa precursor lesions, prostate intraepithelial neoplasia; however, it is not sufficient for PCa development. Double deficiency of Pten and Smad4 leads to a high incidence of metastatic PCa. Targeted deletion of Pten in castration-resistant Nkx3-1-expressing cells results in rapid carcinoma formation after androgen-mediated regeneration, indicating that progenitor cells with luminal characteristics can play a role in initiation of PCa. Transgenic mice with activated oncogenes, growth factors, and steroid hormone receptors or inactivated tumor suppressors continue to provide insights into disease progression from initiation to metastasis. Further development of new PCa models with spatial and temporal regulation of candidate gene expression will probably enhance our understanding of the complex events that lead to PCa initiation and progression, thereby invoking novel strategies to combat this common disease in men.

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Kelly Brewer, Jessica Costa-Guda, and Andrew Arnold

Primary hyperparathyroidism (PHPT) is a common endocrine disorder characterized by dysregulation of parathyroid hormone release. The large majority of PHPT cases are attributable to sporadic, single-gland parathyroid adenoma, in which MEN1 and CCND1/cyclin D1 are the most well-established drivers of tumorigenesis. Sporadic parathyroid carcinoma, which appears to mostly arise through molecular pathways distinct from those causing benign parathyroid tumors, is rare and is most frequently driven by mutational inactivation of the CDC73 (HRPT2) tumor suppressor gene. Targeted investigation of suspected tumor driver genes, as well as unbiased whole-genome or exome sequencing of small cohorts, have revealed additional novel candidate tumor genes in sporadic parathyroid neoplasia, generally at modest or low mutational frequencies consistent with marked molecular genetic heterogeneity from tumor to tumor. The ability of these additional candidates to participate in the pathogenic process of driving parathyroid tumorigenesis in vivo largely remains to be demonstrated experimentally. This review will summarize the molecular genetic abnormalities identified to date in sporadic PHPT and discuss the strength of evidence for their proposed roles in parathyroid tumor formation.

Free access

Kerong Shi, Vaishali I Parekh, Swarnava Roy, Shruti S Desai, and Sunita K Agarwal

The multiple endocrine neoplasia type 1 (MEN1) syndrome is caused by germline mutations in the MEN1 gene encoding menin, with tissue-specific tumors of the parathyroids, anterior pituitary, and enteropancreatic endocrine tissues. Also, 30–40% of sporadic pancreatic endocrine tumors show somatic MEN1 gene inactivation. Although menin is expressed in all cell types of the pancreas, mouse models with loss of menin in either pancreatic α-cells, or β-cells, or total pancreas develop β-cell-specific endocrine tumors (insulinomas). Loss of widely expressed tumor suppressor genes may produce tissue-specific tumors by reactivating one or more embryonic-specific differentiation factors. Therefore, we determined the effect of menin overexpression or knockdown on the expression of β-cell differentiation factors in a mouse β-cell line (MIN6). We show that the β-cell differentiation factor Hlxb9 is posttranscriptionally upregulated upon menin knockdown, and it interacts with menin. Hlxb9 reduces cell proliferation and causes apoptosis in the presence of menin, and it regulates genes that modulate insulin level. Thus, upon menin loss or from other causes, dysregulation of Hlxb9 predicts a possible combined mechanism for β-cell proliferation and insulin production in insulinomas. These observations help to understand how a ubiquitously expressed protein such as menin might control tissue-specific tumorigenesis. Also, our findings identify Hlxb9 as an important factor for β-cell proliferation and insulin regulation.

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Nancy D Perrier, Andrew Arnold, Jessica Costa-Guda, Naifa L Busaidy, Ha Nguyen, Hubert H Chuang, and Maria Luisa Brandi

This report summarizes published data on parathyroid cancer, with the inclusion of topics discussed at MEN2019: 16th International Workshop on Multiple Endocrine Neoplasia, 27–29 March 2019, Houston, TX, USA. An expert panel on parathyroid cancer was constituted by the Steering Committee to address key questions in the field. The objectives were to recap open forum discussion of interested parties from multiple disciplines. The expert panel met in a closed session to consult on the data to be highlighted on the evidence-based results and on the future directions. Preceding the Conference, members of the expert panel conducted an extensive literature search. All presentations were based upon the best peer-reviewed information taking into account the historical and current literature. Questions were developed by the expert panel on parathyroid carcinoma. A comprehensive literature search for relevant studies was undertaken. This report represents the expert panel’s synthesis of the conference material placed in a context designed to be relevant to clinicians and those engaged in cutting-edge studies of parathyroid carcinoma. This document not only provides a summary of our current knowledge but also places recent advances in its management into a context that should enhance future advances in our understanding of parathyroid carcinoma.