Exploring the tumors of multiple endocrine neoplasia type 1 in mouse models for basic and preclinical studies.
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ABSTRACT:
SUBMITTER: Agarwal SK
PROVIDER: S-EPMC4327775 | biostudies-literature | 2014
REPOSITORIES: biostudies-literature
Publications
Exploring the tumors of multiple endocrine neoplasia type 1 in mouse models for basic and preclinical studies.
International journal of endocrine oncology 20140101 2
Most patients (70-90%) with the multiple endocrine neoplasia type 1 (MEN1) syndrome possess germline heterozygous mutations in <i>MEN1</i> that predisposes to tumors of multiple endocrine and nonendocrine tissues. Some endocrine tumors of the kinds seen in MEN1 that occur sporadically in the general population also possess somatic mutations in <i>MEN1</i>. Interestingly, the endocrine tumors of MEN1 are recapitulated in mouse models of <i>Men1</i> loss that serve as a valuable resource to unders ...[more]
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Project description:Multiple endocrine neoplasia type 1 (MEN1) is an autosomal-dominant tumor syndrome characterized by the occurrence of tumors in multiple endocrine tissues and nonendocrine tissues. The three main endocrine tissues most frequently affected by tumors are parathyroid (95%), enteropancreatic neuroendocrine (50%) and anterior pituitary (40%). Tumors are caused by a heterozygous germline-inactivating mutation in the MEN1 gene (1st hit) followed by somatic inactivating mutation or loss of the normal copy of the gene (2nd hit), leading to complete loss of function of the encoded protein menin. Most of the disease features and tumors are recapitulated in mouse models with heterozygous germline loss of the Men1 gene. Also, tissue-specific tumors are observed in mouse models with homozygous somatic loss of the Men1 gene specifically in MEN1-associated endocrine tissues. Hence, mouse models could serve as possible surrogates for studying MEN1 and related states. To gain insights into MEN1 pathophysiology, menin-interacting partners and pathways have been identified to investigate its tumor suppressor and other functions. Also, the 3D crystal structure of menin has been deciphered which could be useful to reveal the relevance of MEN1 gene mutations and menin's interactions. This chapter covers clinical, genetic and basic findings about the MEN1 syndrome, MEN1 gene and its product protein menin.
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Project description:Multiple Endocrine Neoplasia type 1 (MEN1) is a rare autosomal dominant hereditary cancer syndrome presented mostly by tumours of the parathyroids, endocrine pancreas and anterior pituitary, and characterised by a very high penetrance and an equal sex distribution. It occurs in approximately one in 30,000 individuals. Two different forms, sporadic and familial, have been described. The sporadic form presents with two of the three principal MEN1-related endocrine tumours (parathyroid adenomas, entero-pancreatic tumours and pituitary tumours) within a single patient, while the familial form consists of a MEN1 case with at least one first degree relative showing one of the endocrine characterising tumours. Other endocrine and non-endocrine lesions, such as adrenal cortical tumours, carcinoids of the bronchi, gastrointestinal tract and thymus, lipomas, angiofibromas, collagenomas have been described. The responsible gene, MEN1, maps on chromosome 11q13 and encodes a 610 aminoacid nuclear protein, menin, with no sequence homology to other known human proteins. MEN1 syndrome is caused by inactivating mutations of the MEN1 tumour suppressor gene. This gene is probably involved in the regulation of several cell functions such as DNA replication and repair and transcriptional machinery. The combination of clinical and genetic investigations, together with the improving of molecular genetics knowledge of the syndrome, helps in the clinical management of patients. Treatment consists of surgery and/or drug therapy, often in association with radiotherapy or chemotherapy. Currently, DNA testing allows the early identification of germline mutations in asymptomatic gene carriers, to whom routine surveillance (regular biochemical and/or radiological screenings to detect the development of MEN1-associated tumours and lesions) is recommended.
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Project description:BackgroundPatients with multiple endocrine neoplasia type 1 (MEN-1) develop multiple pancreatic neuroendocrine neoplasias (PNENs). Size at diagnosis and growth during follow-up are crucial parameters. According to the WHO 2017, grading is another important parameter. The impact of grading compared to size (WHO 2000) on the clinical course needs to be evaluated.MethodsSixty PNENs of six patients with MEN-1 were retrospectively evaluated.ResultsFifty-one tumors with a diameter of < 20 mm were graded as G1. Two of 9 tumors with diameters of ≥20 mm were graded as G2. Tumor size of ≥20 mm correlated significantly with higher proliferation (p = 0.000617). Lymph node metastases were documented in two patients with a total of 19 tumors. In one patient, all 13 tumors (diameter: 0.4 to 100 mm) were classified as G1. However, metastases were documented in 9/29 lymph nodes. In the other patient, 5 tumors (3.5 to 20 mm) were classified as G1. The sixth tumor (30 mm) was classified as G2 (Ki-67: 8%). Metastases were revealed in 2/20 lymph nodes.ConclusionsTumor size of ≥20 mm seems to correlate with more aggressive MEN-1 related pancreatic disease, regardless of individual proliferation. Tumors ≥20 mm and tumors graded as G2 should be treated surgically regardless of their size.
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Project description:Multiple endocrine neoplasia (MEN) types 1 and 2 are genetic diseases that are inherited as autosomal traits. The major clinical manifestations of multiple endocrine neoplasia type 1 include the so-called "3 P's": parathyroid, pituitary, and pancreatic tumors, including gastroenteroneuroendocrine tumors. Genetic testing can be performed on patients and the potential carriers of the menin gene mutation, but the genotype-phenotype correlation in multiple endocrine neoplasia type 1 is less straightforward than multiple endocrine neoplasia type 2. Most likely, the main advantage of genetic testing in MEN1 is to exclude from further studies those who are negative for the genetic mutation if they belong to a family with a known history of MEN1. In Chile, we started with rearranged during transfection proto-oncogene genetic testing (MEN2) 15 years ago. We carried out a prophylactic total thyroidectomy to prevent medullary thyroid carcinoma in a three-year-old girl who presented with microscopic medullary thyroid carcinoma. More than 90% of the individuals who tested positive using a genetic test achieved a biochemical cure compared with only 27% of patients who receive a clinical diagnosis. Mutations are mainly located in exon 11; the most common is C634W, rather than C634R. Hypertensive crisis was the cause of death in three patients, and extensive distant metastases occurred in nine (including two patients with multiple endocrine neoplasia type 2B) of 14 patients. Earlier recognition of medullary thyroid carcinoma and the other features of the disease, especially pheochromocytoma, will improve the survival rate of patients with multiple endocrine neoplasia.
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Project description:Multiple endocrine neoplasia type 1 (MEN1), a rare tumor syndrome that is inherited in an autosomal dominant pattern, is continuing to raise great interest for endocrinology, gastroenterology, surgery, radiology, genetics, and molecular biology specialists. There have been 2 major clinical practice guidance papers published in the past 2 decades, with the most recent published 8 years ago. Since then, several new insights on the basic biology and clinical features of MEN1 have appeared in the literature, and those data are discussed in this review. The genetic and molecular interactions of the MEN1-encoded protein menin with transcription factors and chromatin-modifying proteins in cell signaling pathways mediated by transforming growth factor β/bone morphogenetic protein, a few nuclear receptors, Wnt/β-catenin, and Hedgehog, and preclinical studies in mouse models have facilitated the understanding of the pathogenesis of MEN1-associated tumors and potential pharmacological interventions. The advancements in genetic diagnosis have offered a chance to recognize MEN1-related conditions in germline MEN1 mutation-negative patients. There is rapidly accumulating knowledge about clinical presentation in children, adolescents, and pregnancy that is translatable into the management of these very fragile patients. The discoveries about the genetic and molecular signatures of sporadic neuroendocrine tumors support the development of clinical trials with novel targeted therapies, along with advancements in diagnostic tools and surgical approaches. Finally, quality of life studies in patients affected by MEN1 and related conditions represent an effort necessary to develop a pharmacoeconomic interpretation of the problem. Because advances are being made both broadly and in focused areas, this timely review presents and discusses those studies collectively.
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Project description:The aim of this study is to evaluate the predictive role of specific clinical factors for the diagnosis of Multiple Endocrine Neoplasia type-1 (MEN1) and type-4 (MEN4) in patients with an initial diagnosis of gastrointestinal, bronchial, or thymic neuroendocrine tumor (NET).MethodsPatients referred to the NET Unit between June 2021 and December 2022 with a diagnosis of NET and at least one clinical criterion of suspicion for MEN1 and MEN4 underwent molecular analysis of the MEN1 and CDKN1B genes. Phenotypic criteria were: (1) age ≤ 40 years; (2) NET multifocality; (3) MEN1/4-associated manifestations other than NETs; and (4) endocrine syndrome related to NETs or pituitary/adrenal tumors.ResultsA total of 22 patients were studied. In 18 patients (81.8%), the first-level genetic test was negative (Group A), while four patients (25%) were positive for MEN1 (Group B). No patient was positive for MEN4. In Group A, 10 cases had only one clinical criterion, and three patients met three criteria. In Group B, three patients had three criteria, and one met all criteria.ConclusionThese preliminary data show that a diagnosis of NET in patients with a negative family history is suggestive of MEN1 in the presence of ≥three positive phenotypic criteria, including early age, multifocality, multiple MEN-associated manifestations, and endocrine syndromes. This indication may allow optimization of the diagnosis of MEN in patients with NET.
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