Happy 20Th Anniversary MEN1: from Positional Cloning to Gene Function Restoration

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F Weber and L M Mulligan Happy 20th anniversary MEN1 24:10 Editorial E7–E11

Happy 20th anniversary MEN1: from positional cloning to gene function restoration

Frank Weber1 and Lois M Mulligan2 Correspondence should be addressed 1Division of Endocrine Surgery, Department of General-, Visceral- and Transplantations Surgery, Medical Faculty, to F Weber University of Duisburg-Essen, Essen, Germany Email 2Division of Cancer Biology and Genetics, Cancer Research Institute, Queen’s University, Kingston, Canada [email protected]

Introduction

With this special anniversary issue on Multiple Endocrine Presbyterian Hospital in New York, USA. The triad Neoplasia Type 1 (MEN1), we celebrate not only history of parathyroid neoplasias, pancreatic neoplasias and in the making, but also the triumph of scientific curiosity pituitary adenoma (the ‘three P’s’ that every medical of numerous researchers and physicians around the student learns), was reported even earlier. Harvey Cushing world. This is particularly poignant these days, as we reported the first case with this classic MEN1 triad in 1927 see isolationism growing stronger: the discovery and (Cushing & Davidoff 1927) and Laurentius Underdahl exploration of ‘Wermer syndrome’ (the original name for published a case series in 1953 (Underdal 1953). MEN1) reminds us once more that the spirit of ingenuity Thus, in the beginning, there was the physician’s thrives most when set free without borders, neither meticulous work recognizing the prototypical philosophical nor physical. abnormalities, and putting those pieces of the Endocrine-Related Cancer Endocrine-Related We feel privileged to guest edit this special anniversary puzzle together. However, detailed knowledge and issue. The review articles cover the broad range of MEN1 characterization of MEN1 was only brought about through syndrome and focus on the clinical (Manoharan et al. 2017, the interactions of physicians, scientists and physician- Marini et al. 2017, Sadowski et al. 2017, van Leeuwaarde scientists in national and international collaborative et al. 2017), translational (Agarwal 2017, Alrezk et al. 2017) initiatives that continue to this day. Their work helped and basic scientific Dreijerink( et al. 2017, Feng et al. 2017, us to understand that MEN1 comprises a variety of Mohr & Pellegata 2017) aspects; therefore, they provide a endocrine as well as non-endocrine manifestations comprehensive update on MEN1. We are delighted that (i.e., adrenocortical neoplasm, thymic and bronchial several of the scientists that pioneered MEN1 research neuroendocrine neoplasms, breast and soft tissue tumors) provided their expertise to this special issue. beyond the parathyroid adenoma, gastrinoma and prolactinoma described originally, and also to understand the genetic, epigenetic and post-translational mechanisms The history of ‘Wermer syndrome’ behind this disorder. The initial foundation that eventually set the stage for the positional cloning of the MEN1 gene took place 63 years 20th anniversary of the MEN1 gene cloning ago, in 1954, when the autosomal dominant inherited co-occurrence of parathyroid hyperplasia, pancreatic Researchers around the globe successfully linked the islet cell tumors and anterior pituitary adenoma was first MEN1 trait to an unknown causative gene at chromosome proposed by the Austrian-born Paul Wermer (Wermer sub-band 11q13 by the late 1990s (Larsson et al. 1988, 1954). During that time, Wermer worked as a physician Bale et al. 1989) and collaborative efforts allowed in the Department of Medicine, Columbia University, the region of interest to be further narrowed down

http://erc.endocrinology-journals.org © 2017 Society for Endocrinology This editorial accompanies a thematic review section on 20 Years of MEN1. DOI: 10.1530/ERC-17-0346 Published by Bioscientifica Ltd. The guest editors for this section were Lois Mulligan and Frank Weber. Printed in Great Britain Downloaded from Bioscientifica.com at 09/28/2021 01:20:31AM via free access

10.1530/ERC-17-0346 Editorial F Weber and L M Mulligan Happy 20th anniversary MEN1 24:10 E8

(Byström et al 1990, Janson et al. 1991, Courseaux controls various biological processes in neuroendocrine et al. 1996). The investigations supported the biallelic organ hemeostasis’. inactivation of the MEN1 tumor suppressor gene Established models are essential to elucidate MENIN following the Knudson two-hit hypothesis (Bale et al. mechanisms and function. Myles Brown and coworkers 1991, Ebrahimi & Sawicki 1997) (Fig. 1). discuss the current cellular models available and the Finally, in 1997, two research groups, the NIH group lack of established model systems based on human cells and the European MEN1 Consortium, identified the (Dreijerink et al. 2017). This aspect is further highlighted MEN1 gene by positional cloning (Chandrasekharappa by an outstanding review provided by Hermine Mohr et al. 1997, Lemmens et al. 1997). We are delighted that and Natalia Pellegata. These authors bring us up-to-date one of the co-authors of this original publication Sunita on the available animal models for MEN1 research and Agarwal, then a postdoctoral fellow at the NIDDK, NIH, provide us with their vision for future developments has graced us with an insightful and comprehensive (Mohr & Pellegata 2017). overview on the genetic aspects of MEN1 and how these The management of patients with MEN1 has changed influence the clinical management of patients with MEN1 dramatically over the last two decades. We are able to (Fig. 2) (Agarwal 2017). control gastric acid hypersecretion due to Zollinger– Myles Brown and coworkers advance from the MEN1 Ellison Syndrome (ZES) as one of the main causes of gene to its protein product MENIN (Dreijerink et al. mortality. Today, patients are more likely to die of local 2017). The authors review exciting recent knowledge or metastatic progression of neuroendocrine neoplasms. on the functional properties of MENIN that ‘links gene- This has a tremendous impact on diagnostic as well as specific transcription factors to chromatin modification surveillance. Gerlof Valk and coworkers give us the in a cell-specific context’. They further explore the physicians’ perspective and take us on a tour of how the emerging opportunities for ‘gene function restoration’ management of MEN1-related symptoms has changed and potential therapeutic intervention of MEN1 over time (van Leeuwaarde et al. 2017). (Dreijerink et al. 2017). Xianxin Hua and coworkers As was true over 60 years ago, comprehensive further unravel the complex interaction of MENIN understanding of the presentation of inherited tumor with several signaling pathways (Feng et al. 2017). They traits is one of the corner stones of treating this disease. provide a comprehensive update on the biochemical While the development of highly effective treatment role and the underlying mechanism of ‘how menin modalities has allowed us to increase the life expectancy Endocrine-Related Cancer Endocrine-Related

1988

Larson et al. 1988

1990 Genetic map of 11q13 1990 Julier et al. 1990 Link to the PYGM locus Byström et al. 1990

1991 Physical map of 11q13 Janson et al. 1991 1996 Integrated map of the MEN1 region Courseaux et al. 1996

1997

Figure 1 ‘Road’ leading to the identification of theMEN1 gene in 1997.

http://erc.endocrinology-journals.org © 2017 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/ERC-17-0346 Printed in Great Britain Downloaded from Bioscientifica.com at 09/28/2021 01:20:31AM via free access Editorial F Weber and L M Mulligan Happy 20th anniversary MEN1 24:10 E9

Endocrine-Related Cancer Endocrine-Related Figure 2 Group photo of the MEN1 gene team outside NIH building 49 where the team met for weekly group meetings. The gene team included (in the front row, from left to right) S Agarwal (NIDDK), Z Zhuang (NCI), S Chandrasekharappa (NHGRI), S Olufemi (NHGRI), S Guru (NHGRI); (in the second row, from left to right) M Kester (NIDDK), M Boguski (NCBI/NLM), Y Kim (NIDDK), S Marx (NIDDK), J Crabtree (NHGRI); (in the third row, from left to right) M Emmert-Buck (NCI), L Debelenko (NCI), J Weisemann (NCBI/NLM), P Manickam (NHGRI); (in the back row, from left to right) A Spiegel (NIDDK), I Lubensky (NCI), C Heppner (NIDDK), L Burns (NIDDK), F Collins (NHGRI). Not shown are L Liotta (NCI), Y Wang and B Roe (University of Oklahoma), and Q Dong (NIDDK, later at University of Sydney, Australia). The image was kindly provided by S Agarwal from ‘The NIH Record’ Newsletter May 20, 1997. Vol. XLIX, No. 10.

of patients with MEN1, several reviews in this series In the same vein, Constantine Stratakis and highlight the importance of genetic counseling (Agarwal coworkers further elucidate the importance of this ‘other’ 2017, Marini et al. 2017, van Leeuwaarde et al. 2017). MEN1 syndrome. In their review, the authors outline In a previous article, Valk and coworkers showed that the genetics, clinical manifestations and management of today, the correct diagnosis of MEN1 frequently remains patients with the closely related MEN4 syndrome, caused substantially delayed. The authors point out that the by germline mutations in the gene (CDKN1B) coding for ‘median lag time’ for diagnosis in family members is p27 that result in the development of parathyroid and 3.5 years and that over 30% of non-index patients already pituitary adenomas (Alrezk et al. 2017). suffer hyperparathyroidism (HPT) or duodeno-pancreatic While the development of hormone assays which neuroendocrine neoplasms (NEN) at the time of diagnosis began in the late 1960s allowed us to better identify (van Leeuwaarde et al. 2016). Furthermore, Valk and patients affected by MEN1-related tumors, modern coworkers discuss in this same review the management of imaging helps us to visualize even hormone-inactive patients with clinical features similar to those observed in tumors at much earlier stages. The review on therapeutic MEN1 patients, but for which mutation analysis has failed approaches and management of MEN1 by Detlef Bartsch to detect MEN1 gene mutations. and coworkers highlight the changes that have taken

place in diagnosis, and in particular, imaging of MEN1- Multiple endocrine neoplasia type 1, aka Wermer associated tumors (Manoharan et al. 2017). The authors syndrome, remains a fascinating tumor syndrome. For discuss the modalities and timing for MEN1 surveillance the clinician, rapid recognition and diagnosis, quality and highlight the development and importance of of life, active surveillance and improvements in genetic novel imaging techniques. Furthermore, since small counseling are emerging as critical aspects of care. Our non-functioning NEN have become the most common diagnostic and therapeutic modalities will further be pancreatic NEN (PNEN), the authors address the question refined to reduce risk and maximize benefit. As we start of how to deal with small pancreatic neoplasms. to understand the functional properties of MENIN, new The concept of active surveillance is discussed not aspects of its functions and implications in disease are only by Bartsch and coworkers but also by other reviews emerging that require further elucidation. Finally, these in this series (Marini et al. 2017, Sadowski et al. 2017, van findings will eventually be translated to further inform Leeuwaarde et al. 2017). A large international collaborative clinical management algorithms and provide us with new initiative has very recently shown that non-functioning therapeutic or even better, preventative, options. PNEN below 2 cm in size harbor a low oncologic property. During the study period, active surveillance of patients with these tumors increased from 36% (1997–2007) to Declaration of interest The authors declare that there is no conflict of interest that could be 64% (2007–2013). Importantly, only 36% of patients perceived as prejudicing the impartiality of this editorial. under surveillance required surgery during follow-up (Triponez et al. 2017).

MEN1 management has shifted to patient-centered, Funding individualized treatment and the follow-up management This work did not receive any specific grant from any funding agency in is becoming more and more important. Treatment options the public, commercial or not-for-profit sector. are carefully compared for risk and benefit, and tailored to patient needs by an interdisciplinary tumor board together with the patient in a ‘shared decision-making’ process, as References van Leeuwaarde and coworkers state in their review. This Agarwal SK 2017 The future: genetics advances in MEN1 therapeutic concept is further expanded upon by Maria Luisa Brandi approaches and management strategies. Endocrine-Related Cancer 24 T119–T134. (doi:10.1530/ERC-17-0199) and coworkers, who provide us with an outstanding Endocrine-Related Cancer Endocrine-Related Alrezk R, Hannah-Shmouni F & Stratakis C 2017 MEN4 and CDKN1B review of the evolution of clinical practice guidelines over mutations: the latest of the MEN syndromes. Endocrine-Related Cancer time that sets the stage for discussions of how quality of 24 T195–T208. (doi:10.1530/ERC-17-0243) Bale SJ, Bale AE, Stewart K, Dachowski L, McBride OW, Glaser T, Green life is affected in MEN1 patients. This review outlines how JE 3rd, Mulvihill JJ, Brandi ML, Sakaguchi K, et al. 1989 Linkage the individualization and personalization of treatment analysis of multiple endocrine neoplasia type 1 with INT2 and other options, especially surgical intervention, affects quality of markers on chromosome 11. Genomics 4 320–322. (doi:10.1016/0888-7543(89)90336-4) life (Marini et al. 2017). Bale AE, Norton JA, Wong EL, Fryburg, PN, Maton PN, Oldfield EH, Frédéric Triponez and coworkers focus on surgical Streeten E, Aurbach GD, Brandi ML, Friedman E, et al. 1991 Allelic management of patients with MEN1. In particular, they loss on chromosome 11 in herditary and sporadic tumors related to familial multiple endocrine neoplasia type 1. Cancer Research 51 highlight the important management of neuroendocrine 1154–1157. tumors (pancreatic, thymic and bronchial) and of Byström C, Larsson C, Blomberg C, Sandekin K, Falkmer U, Skogseid B, aggressive/metastatic disease (Sadowski et al. 2017). The Oberg K, Werner S & Nordenskjöld M 1990 Localization of the MEN1 gene to a small region within chromosome 11q13 by deletion most frequent endocrinopathy in MEN1 is HPT that mapping in tumors. PNAS 87 1968–1972. occurs in over 80% of patients. Brandi and coworkers Courseaux A, Grosgeorge J, Gaudray P, Pannett AA, Forbes SA, discuss the management of these patients and how these Williamson C, Bassett D, Thakker RV, Teh BT, Farnebo F, et al. 1996 Definition of the minimal MEN1 candidate area based on a 5-Mb treatment algorithms have changed over time (Marini integrated map of proximal 11q13. The European Consortium on et al. 2017). For pituitary adenoma, which occurs in MEN1, (GENEM 1; Groupe d’Etude des Néoplasies Endocriniennes 10% of patients with MEN1, there are insufficient data Multiples de type 1). Genomics 37 354–365. (doi:10.1006/ geno.1996.0570) at this point to propose a surgical management that Cushing H & Davidoff LM 1927 Studies in acromegaly V. The pathological differs from that of sporadic pituitary tumors. Similarly, finding in four autopsied cases of acromegaly with a discussion of their the surgical treatment of other MEN1-associated tumors significance. Monograph. New York, NY, USA: Rockefeller Institute for Medical Research. broadly follow the treatment modalities for their sporadic Chandrasekharappa SC, Guru SC, Manickam P, Olufemi SE, Collins FS, counterpart. Emmert-Buck MR, Debelenko LV, Zhuang Z, Lubensky IA, Liotta LA,

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Received in final form 15 August 2017 Accepted 17 August 2017 Endocrine-Related Cancer Endocrine-Related