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Clues for Genetic Anticipation in Multiple Endocrine Neoplasia Type 1

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Clues for Genetic Anticipation in Multiple Endocrine Neoplasia Type 1 Copyedited by: oup CLINICAL RESEARCH ARTICLE Clues For Genetic Anticipation In Multiple Endocrine Neoplasia Type 1 Downloaded from https://academic.oup.com/jcem/article-abstract/105/7/dgaa257/5836321 by Erasmus Universiteit Rotterdam user on 08 June 2020 Medard F.M. van den Broek,1 Bernadette P.M. van Nesselrooij,2 Carolina R.C. Pieterman,1 Annemarie A. Verrijn Stuart,3 Annenienke C. van de Ven,4 Wouter W. de Herder,5 Olaf M. Dekkers,6 Madeleine L. Drent,7 Bas Havekes,8 Michiel N. Kerstens,9 Peter H. Bisschop,10 and Gerlof D. Valk1 1Department of Endocrine Oncology, University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands; 2Department of Medical Genetics, Wilhelmina Children’s Hospital, University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands; 3Department of Pediatric Endocrinology, Wilhelmina Children’s Hospital, University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands; 4Department of Endocrinology, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands; 5Department of Internal Medicine, Erasmus Medical Center, 3000 CA Rotterdam, The Netherlands; 6Departments of Endocrinology and Metabolism and Clinical Epidemiology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands; 7Department of Internal Medicine, Section of Endocrinology, Amsterdam UMC, location VU University Medical Center, 1007 MB Amsterdam, The Netherlands; 8Department of Internal Medicine, Division of Endocrinology, Maastricht University Medical Center, 6202 AZ Maastricht, The Netherlands; 9Department of Endocrinology, University Medical Center Groningen, 9700 RB Groningen, The Netherlands; and 10Department of Endocrinology and Metabolism, Amsterdam UMC, location Academic Medical Center, 1100 DD Amsterdam, The Netherlands ORCiD numbers: 0000-0002-4656-2960 (M. F.M. van den Broek); 0000-0002-1333-7580 (O. M. Dekkers). Context: Multiple endocrine neoplasia type 1 (MEN1) is a rare autosomal dominant hereditary disease caused by the loss of function of the MEN1 gene, a tumor-suppressor gene that encodes the protein menin. It is characterized by the occurrence of primary hyperparathyroidism (pHPT), duodenopancreatic neuroendocrine tumors (dpNET), pituitary tumors (PIT), adrenal adenomas, and bronchopulmonary (bp-NET), thymic, and gastric neuroendocrine tumors. More insight into factors influencing the age-related penetrance of MEN1 manifestations could provide clues for more personalized screening programs. Objective: To investigate whether genetic anticipation plays a role in the largest known MEN1 families in the Netherlands. Methods: All Dutch MEN1 families with ≥ 10 affected members in ≥ 2 successive generations were identified. Age at detection of the different MEN1-related manifestations were compared among generations using regression analyses adjusted for competing risks. To correct for the beneficial effect of being under surveillance, manifestations occurring during surveillance were also separately compared. Results: A total of 152 MEN1 patients from 10 families were included. A significantly decreased age at detection of pHPT, dpNET, PIT, and bp-NET was found in successive generations (P < 0.0001). Adjusted analyses led to the same results. Conclusions: These results suggest the presence of genetic anticipation. However, due to a risk of residual bias, the results must be interpreted with caution. After independent validation ISSN Print 0021-972X ISSN Online 1945-7197 Printed in USA © Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals. [email protected] Received 24 February 2020. Accepted 8 May 2020. First Published Online 12 May 2020. Corrected and Typeset 28 May 2020. doi:10.1210/clinem/dgaa257 J Clin Endocrinol Metab, July 2020, 105(7):1–10 https://academic.oup.com/jcem 1 Copyedited by: oup 2 van den Broek et al Genetic Anticipation in MEN 1 J Clin Endocrinol Metab, July 2020, 105(7):1–10 in other cohorts and further translational research investigating the molecular mechanisms explaining this phenomenon in MEN1, the results might add to future, more personalized, screening protocols and earlier screening for future generations of MEN1 patients. (J Clin Endocrinol Metab 105: 1–10, 2020) Freeform/Key Words: age of onset, genetic anticipation, multiple endocrine neoplasia type 1, Downloaded from https://academic.oup.com/jcem/article-abstract/105/7/dgaa257/5836321 by Erasmus Universiteit Rotterdam user on 08 June 2020 surveillance ultiple Endocrine Neoplasia type 1 (MEN1) is cancer such as dyskeratosis congenita, Lynch Syndrome, M a rare hereditary disease caused by loss of func- Li-Fraumeni syndrome, von Hippel-Lindau syndrome, tion of the MEN1 gene. The MEN1 gene is a tumor and hereditary breast and ovarian cancer syndrome suppressor gene that encodes the protein menin. It has (10–14). In these syndromes the genetic defect is trans- an estimated prevalence of 2–10 per 100000 and is in- mitted without alterations. Partly due to the lack of gen- herited in an autosomal dominant pattern (1). Although erally accepted explanatory biological mechanism and a wide variety of manifestations have been described, a high risk of bias in this field of research, some pub- most MEN1 patients suffer from (1) primary hyperpara- lications suggested this observation to be the result of thyroidism (pHPT) (90–95%), (2) duodenopancreatic different forms of bias (15–17). To our knowledge, data neuroendocrine tumor (dpNET) (35–75%), (3) anterior about genetic anticipation within MEN1 families are pituitary tumors (PIT) (20–65%), (4) adrenal aden- limited to 1 study, describing a MEN1 family of 5 gener- omas (ADR) (11–35%), and (5) bronchopulmonary ations with clinical expression suggestive of anticipation (bp-NET), thymic (th-NET), and gastric neuroendo- (18). The aim of this nationwide study is to investigate crine tumors (20–30%) (2, 3). MEN1 mutations have whether genetic anticipation plays a role in the largest a high penetrance, and patients with MEN1 suffer from known MEN1 families in the Netherlands. high morbidity and a decreased life expectancy (4). In particular, th-NET and pancreatic NET are main causes of MEN1-related death (4, 5). Methods In order to detect MEN1 manifestations in an early Patient selection stage, periodic screening of MEN1 patients is advised. Since the discovery of the MEN1 gene in 1997 until re- The present clinical practice guidelines advise to start cently, all genetic testing for MEN1 gene abnormalities in the screening for a number of manifestations at the age of Netherlands has been performed centrally at the University 5 in all MEN1 mutation carriers, and to expand the Medical Center Utrecht. All potential Dutch MEN1 patients and mutation carriers referred for genetic testing between screening with age (6). Despite numerous efforts, no January 1998 and December 2017 were identified. Pedigree direct genotype–phenotype correlation has been found information was retrieved from medical records and checked to date (7). Although minor familial clustering of spe- using the Dutch Municipal Resident Registration. Mutation- cific tumors has been described (8), in general both a positive MEN1 families were selected if these families com- considerable phenotypic variability of manifestations, prised at least 10 affected members in 2 or more successive as well as variable age at diagnosis, have been reported generations. (7). More insight into factors influencing the age-related penetrance of MEN1 manifestations could provide clues Retrieval of clinical information Clinical information about affected family members for more personalized screening programs for MEN1 was obtained using the national MEN1 database of the mutation carriers, potentially leading to a decrease in Dutch MEN1 study group (DMSG). This database con- patient (and parental) burden, as well as lower health tains longitudinally collected clinical information of pa- care costs. tients ≥ 16 years of age at the end of 2017 and treated at 1 Genetic anticipation refers to the phenomenon of of the Dutch university medical centers between 1990 and 2017. The study cohort includes ≥ 90% of the total Dutch decreased age of disease onset or an increased disease MEN1 population. Data of all the patients were collected severity in successive generations. It is best known in from every quarter of every available year of follow-up, neuropsychiatric diseases such as Huntington’s disease from 1990 to 2017. Furthermore, data concerning the oc- and myotonic dystrophy. In these diseases, trinucleotide currence of MEN1-related manifestations before 1990 and repeat expansions (“growing genes”) are responsible for before 16 years of age were included as well. Detailed in- the phenotype of genetic anticipation, as the length of formation on the DMSG database methods have been de- scribed previously (19). the repeat is transmitted in an unstable way and can Patients deceased before 1990, < 16 years of age on be influenced by the parental origin (9). More recently, December 31, 2017, or patients whose clinical or pedigree in- anticipation was also described in forms of heritable formation was lacking were excluded from this study. Copyedited by: oup doi:10.1210/clinem/dgaa257 https://academic.oup.com/jcem 3 Definitions of MEN1 manifestations performed in 134 patients (88%), and a mutation (or In order to determine the exact prevalence and time of diag- affected allele) was found in all of these cases. Main nosis of an MEN1-related manifestation, the following defin- features of the 10 families are described in
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