Clinical Genetic Testing and Early Surgical Intervention in Patients With Multiple Endocrine Neoplasia Type 1 (MEN 1)

The multiple endocrine neoplasia type 1 (MEN 1) syndrome is characterized by the development of hyperparathyroidism due to multiglandular parathyroid disease (95% to 100% of patients), benign and malignant neuroendocrine tumors of the pancreas and duodenum (35% to 75%), and adenomas of the anterior pituitary (15% to 30%). Other neoplasms associated with MEN 1 include foregut (thymic and bronchial) carcinoids, multiple lipomas, nodular adrenocortical hyperplasia, cutaneous angiofibromas, and ependymomas of the central nervous system. The clinical expression of endocrine disease in patients with MEN 1 most often begins in the third or fourth decade, with the onset of overt disease being rare before age 10 years.1 In keeping with its autosomal dominant inheritance pattern, males and females are affected equally. The MEN 1 syndrome has been described in diverse geographic regions and ethnic groups, and no racial predilection has been demonstrated. Endocrine tumors in patients with MEN 1 cause symptoms either due to overproduction of a specific hormone or the local mass effects and/or malignant progession of the neoplasm. Previously, complications related to hormone excess, such as severe ulcer disease or hypoglycemia, were the most frequent presenting complaints2 and not infrequently resulted in patient deaths. Currently, the principal cause of mortality in patients with MEN 1 is the malignant progression of the neuroendocrine tumors of the pancreas, duodenal gastrinomas, and thymic or bronchial carcinoids.3,4 Unique characteristics of neoplasms that arise in association with an inherited cancer syndrome include a preneoplastic hyperplasia within the affected tissue (eg, islet cell hyperplasia), the development of multiple tumors within a target tissue, and the potential for development of tumors in more than 1 target tissue. Furthermore, in the setting of a familial cancer syndrome, patients develop tumors at a much younger age than patients who develop sporadic tumors of the same tissue type. In keeping with the “two-hit” model of tumorigenesis for a putative tumor suppressor gene, this earlier age-of-onset is due to the fact that 1 mutation is inherited in the germline and only 1 other event is necessary to inactivate the remaining wild-type allele and result in tumor initiation. Therefore, patients inheriting an MEN1 gene mutation have a propensity to develop multiple tumors at a young age when they are otherwise healthy and active. Although many of these endocrine neoplasms are either benign or may follow an indolent course, a subset may metastasize early to regional lymph nodes, liver, or distant sites and be life-limiting. The clinical management of these tumors is complicated by the difficulty in localizing small tumors early on routine imaging tests, the relative lack of specific and sensitive tumor markers for, and uncertainty about the expected natural history of small tumors. Most importantly, in contrast to other familial cancer syndromes and the tissue at principal malignant risk, such as multiple endocrine neoplasia type 2 (thyroid) and familial adenomatous polyposis (colon), a prophylactic total extirpation of the target tissue at most risk for malignant change (pancreas) carries inordinate risk of morbidity and mortality in an otherwise young, healthy patient. Germline mutations in the MEN1 tumor suppressor gene are responsible for the MEN 1 syndrome.5 The MEN1 tumor suppressor gene encodes a 610 amino acid protein product termed menin. Menin is expressed in diverse tissues, including lymphocytes, pancreas, brain, and testes, and it is highly conserved evolutionarily. Menin is predominately a nuclear protein6 that has been shown to bind to JunD (a member of the AP-1 transcription factor family), as well as other proteins, and it is postulated to repress JunD-mediated transcription.7,8 The specific tumor-suppressing role of menin has not yet been elucidated. The disease-associated germline mutations that occur in the MEN1 tumor suppressor gene are diverse and include missense, nonsense, frameshift, deletion, and mRNA splicing defects which may be dispersed throughout the coding and noncoding (intronic) portions of the gene.9–13 Furthermore, there are almost as many unique mutations as there are families reported with MEN 1. To date, over 300 specific germline mutations have been described in families with MEN 1.14 The diverse nature of MEN1 disease mutations has important implications for the development of a comprehensive clinical genetic test. We sought to develop a comprehensive program for clinical genetic testing in a large group of MEN 1 families, with the ultimate aim of early tumor detection and surgical intervention. The essential components this study include translation of molecular genetic findings in the research laboratory to an accredited clinical Molecular Diagnostic Laboratory and the development of a program of formal genetic counseling for all participants. Genetically positive patients undergo focused biochemical screening for development of the most clinically significant tumors, with the aim of early tumor detection and surgical intervention.