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1/10. A novel germline mutation of multiple endocrine neoplasia type 1 (MEN1) gene in a Japanese MEN1 patient and her daughter.

    Familial multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant inherited disorder characterized by tumors of the parathyroid, anterior pituitary and gastro-entero-pancreatic endocrine tissues. The MEN1 gene has recently been cloned and its germline mutations have been considered to play an important role in the tumorigenesis of MEN1. We analyzed a Japanese MEN1 patient and her daughter for germline mutations of the MEN1 gene. The proband (60 y.o.) had primary hyperparathyroidism (PHP) and gastrinoma, and her daughter (30 y.o.) had prolactinoma. Clinical examinations revealed no evidence of PHP in the daughter. We identified a novel heterozygous germline mutation (712 A del) at codon 201 in exon 3 of the MEN1 gene in the proband. Restriction digestion analysis revealed the same mutation pattern in her daughter. These findings suggest that this family has familial MEN1 including a rare case of MEN1 with a single lesion of the pituitary. Genetic examinations are useful as diagnostic tools for any rare or variant case of familial MEN1.
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ranking = 1
keywords = tumorigenesis
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2/10. multiple endocrine neoplasia type 1: atypical presentation, clinical course, and genetic analysis of multiple tumors.

    multiple endocrine neoplasia type 1 (MEN1) is characterized by the development of endocrine tumors of the parathyroid and pituitary glands, pancreas, and duodenum. Less frequently occurring tumors associated with MEN1 include non-endocrine tumors such as lipomas and angiofibromas. An increased incidence of thyroid neoplasms, leiomyomas, adrenal cortical hyperplasia, hepatic focal nodular hyperplasia, and renal angiomyolipoma has been noted in the MEN1 population. The pathogenesis of non-neuroendocrine tumors in MEN1 is unknown. We report a complex clinical course and a detailed morphologic and genetic analysis of a series of tumors that developed in a patient with MEN1. All tumors were microdissected and analyzed for loss of heterozygosity of the MEN1 gene. A germline mutation of the MEN1 gene was detected, and deletions of the MEN1 gene were consistently detected in multiple neuroendocrine tumors involving the parathyroid glands and the pancreas and a hepatic neuroendocrine tumor metastasis, as predicted by Knudson's "two hit" hypothesis. Two hits of the MEN1 gene were also detected in esophageal leiomyoma tissue, suggesting that tumorigenesis was directly related to the patient's underlying MEN1. In contrast, follicular thyroid adenoma, papillary thyroid carcinoma, hepatic focal nodular hyperplasia, and adrenal cortical hyperplasia consistently showed retained heterozygosity of the MEN1 gene with flanking markers and an intragenic marker. Therefore, these tumors appear to develop along pathogenetic pathways that are different from classical MEN1-associated tumors.
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ranking = 1
keywords = tumorigenesis
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3/10. Pituitary macroadenoma in a 5-year-old: an early expression of multiple endocrine neoplasia type 1.

    multiple endocrine neoplasia type 1 (men 1) is associated with parathyroid, enteropancreatic, pituitary, and other tumors. The MEN1 gene, a tumor suppressor, is located on chromosome 11. Affected individuals inherit a mutated MEN1 allele, and tumorigenesis in specific tissues follows inactivation of the remaining MEN1 allele. men 1-associated endocrine tumors usually become clinically evident in late adolescence or young adulthood, as high levels of PTH, gastrin, or PRL. Because each of these tumors can usually be controlled with medications and/or surgery, men 1 has been regarded mainly as a treatable endocrinopathy of adults. Unlike in men 2, early testing of children in men 1 families is not recommended. We report a 2.3-cm pituitary macroadenoma in a 5-yr-old boy with familial men 1. He presented with growth acceleration, acromegaloid features, and hyperprolactinemia. We tested systematically to see whether his pituitary tumor had causes similar to or different from a typical men 1 tumor. Germ line dna of the propositus and his affected relatives revealed a heterozygous point mutation in the MEN1 gene, which leads to a His139Asp (H139D) amino acid substitution. The patient had no other detectable germ-line mutations on either MEN1 allele. dna sequencing and fluorescent in situ hybridization with a MEN1 genomic dna sequence probe each demonstrated one copy of the MEN1 gene to be deleted in the pituitary tumor and not in normal dna, proving MEN1 "second hit" as a tumor cause. Gsalpha mutation, common in nonhereditary GH-producing tumors, was not detected in this tumor. We conclude that this pituitary macroadenoma showed molecular genetic features of a typical men 1-associated tumor. This patient represents the earliest presentation of any morbid endocrine tumor in men 1. A better understanding of early onset men 1 disease is needed to formulate recommendations for early men 1 genetic testing.
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ranking = 1
keywords = tumorigenesis
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4/10. Multiple endocrine neoplasia (men)--an overview and case report--patient with sporadic bilateral pheochromocytoma, hyperparathyroidism and marfanoid habitus.

    The multiple endocrine neoplasia syndromes are divided into two categories: men type I and men type II. The men type II syndrome is further divided into men IIa and men IIb. The syndromes are characterized by benign and malignant changes in two or more endocrine organs, as well as incidental changes in nervous, muscular and connective tissue. Two main forms can be distinguished: the men-I syndrome with hyperplasia of the parathyroid gland, accompanied by islet cell tumor and pituitary adenoma; the men-II syndrome with medullary thyroid carcinoma in combination with bilateral pheochromocytoma and hyperplasia of the parathyroid gland (men IIa), while type IIb is characterized by the additional appearance of neurocutaneous manifestations without primary hyperparathyroidism. Characteristics shared by these syndromes include the involved cell type, most of the tumors are composed of one or more specific polypeptide- and biogenic amine-producing cell types (APUD--amine precursor uptake and decarboxylation). The second characteristic is the increased incidence in certain families. The hereditary component is autosomal dominant with variable expression but high penetrance. Mechanisms of tumorigenesis differ in these syndromes. While men I is caused by an inherited mutation of a tumor suppressor gene, menin, located on the long arm of chromosome 11, men II is caused by activation of the RET proto-oncogene. We have reported the case of a young man exhibiting bilateral pheochromocytoma. In addition, the patient showed mild primary hyperparathyroidism and marfanoid habitus, all these stigmata usually being part of the men-II syndrome. Although this described patient showed a phenotypic mixture of the men-IIa and men-IIb syndrome, the genetic analysis for men II and von-Hippel-Lindau gene did not reveal any pathologic mutations, the endocrine disorders described here are not related to multiple endocrine neoplasia syndromes.
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ranking = 1
keywords = tumorigenesis
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5/10. Somatic mutations of the MEN1 gene and microsatellite instability in a case of tertiary hyperparathyroidism occurring during high phosphate therapy for acquired, hypophosphatemic osteomalacia.

    Somatic mutations of the men type 1 (MEN1) gene were recently shown to be responsible for tumorigenesis in 13-26% of sporadic, nonfamilial primary hyperparathyroidism. However, it is unknown whether these mutations are also involved in tumorigenesis of parathyroid glands occurring during high phosphate therapy for hypophosphatemic rickets or osteomalacia. A male patient with adult-onset, hypophosphatemic osteomalacia had been treated with 1alpha-OHD3 and oral phosphate for 13 yr when tertiary hyperparathyroidism developed. After total resection of four enlarged parathyroid glands and autotransplantation of a hyperplastic gland, the patient has continued to do well for the last 2 yr. sequence analysis of the coding exons of MEN1 gene revealed a 36-bp deletion with a 2-bp insertion (exon 2) in the right upper parathyroid gland accompanied with loss of heterozygosity at 11q13 locus and a heterozygous mutation of 2-bp deletion (AG) in exon 10 in the right lower gland, in which microsatellite instability was also found. No MEN1 gene mutation was detected in the other two hyperplastic parathyroid glands or in the peripheral blood. These findings indicate that MEN1 gene mutations contributed to tumorigenesis of the right upper parathyroid gland in this case of phosphate-induced tertiary hyperparathyroidism. Very recently a bone tumor was found in the right femoral neck, and the tumor (chondroblastoma) was resected.
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ranking = 3
keywords = tumorigenesis
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6/10. Familial adenomatous polyposis associated with multiple endocrine neoplasia type 1-related tumors and thyroid carcinoma: a case report with clinicopathologic and molecular analyses.

    We describe a sporadic case with familial adenomatous polyposis, multiple endocrine neoplasia type 1 (MEN1)-related tumors (an endocrine cell tumor of the pancreas and bilateral parathyroid tumors), and a papillary thyroid carcinoma. To clarify how mutations of the adenomatous polyposis coli ( APC ) gene and the MEN1 gene, responsible for familial adenomatous polyposis and MEN1, respectively, might have contributed to tumorigenesis in this case, we studied germline mutations in both genes and loss of heterozygosity at their genetic loci in multiple lesions. In addition, we performed immunohistochemistry for beta-catenin, associated with the function of the APC gene. A germline mutation was found in the APC gene but not in the MEN1 gene. Normal allelic loss at the APC gene locus was observed in bilateral parathyroid tumors. Immunohistochemical staining of beta-catenin demonstrated accumulation in the cytoplasm in addition to membrane staining in all analyzed tumors and a strong nuclear reaction in the endocrine cell tumor of the pancreas. The presence of normal allelic deletions of the APC gene in bilateral parathyroid tumors and nuclear staining of beta-catenin in the pancreatic tumor in addition to the germline mutations suggests that functional loss of the APC gene played an important role not only in familial adenomatous polyposis but also in the MEN1-related tumors in this case.
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ranking = 1
keywords = tumorigenesis
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7/10. A novel missense mutation of the MEN1 gene in a multiple endocrine neoplasia type 1 patient associated with carcinoid syndrome.

    We report a multiple endocrine neoplasia type 1 (MEN1) patient associated with carcinoid syndrome. A 50-year-old woman had parathyroid hyperplasia with primary hyperparathyroidism, a pancreatic tumor and carcinoid tumors in the liver and duodenum. The primary lesion of the carcinoid was probably the bronchus. Direct sequencing analysis revealed a novel missense mutation at codon 342 in exon 7 causing an amino acid change from alanine to proline (A342P) of the MEN1 gene. loss of heterozygosity (LOH) was also detected in the resected parathyroid tissue. This mutation appeared to play an important role in the tumorigenesis of the endocrine tissues in the present case.
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ranking = 1
keywords = tumorigenesis
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8/10. Thymic carcinoid in multiple endocrine neoplasia 1: genotype-phenotype correlation and prevention.

    Thymic carcinoid is a rare multiple endocrine neoplasia type 1 (MEN1)-associated tumour that is a major cause of death in MEN1 patients. Here, we describe a previously unreported MEN1 family in which two siblings presented with malignant thymic carcinoids. All six siblings share a novel nonsense mutation Q395X on exon 8 of the MEN1 gene. The index patient developed a thymic carcinoid despite an earlier prophylactic transcervical thymectomy, and one other sibling had an incidental malignant thymic carcinoid discovered following prophylactic thymectomy, both cases demonstrating the weakness and strength of this surgical approach. We then review the spectrum of germline MEN1 mutations associated with thymic carcinoids to evaluate the possibility of a genotype-phenotype correlation. In the 22 separate MEN1 families with thymic carcinoids, all but two (91%) have mutations coding for a truncated protein. There is clearly a high prevalence of truncating mutations in MEN1-related thymic carcinoids although when compared with the prevalence of truncating mutations in all reported MEN1 mutations, it is not statistically significant (P = 0.39). Further studies are warranted to evaluate pathways of tumorigenesis of thymic carcinoids with regard to loss of function of menin.
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ranking = 1
keywords = tumorigenesis
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9/10. multiple endocrine neoplasia type 1 (MEN1): LOH studies in a affected family and in sporadic cases.

    Multiple endocrine neoplasia (Menl) is an autosomai dominant hereditary trait characterized by tumors of endocrine tissues. The MEN1 gene maps to chromosome llql3, has been recently isolated, and encodes a protein termed menin that is ubiquitously expressed. This gene is likely to be a tumor suppressor gene, with tumors developing after the inactivation of both copies of the gene in a single cell. In agreement with this, 11q-deletions (loss of heterozygosity) are frequently found in neoplasms from MEN1 patients. In this study, dna from family-members was extracted and analysed for 10 microsatellites flanking the MEN1-gene on chromosome 11q. SSCP was used to determine the presence of MEN1-mutations in several patients. dna was extracted from paraffin blocks containing tissue from 10 parathyroid tumors (4 familial and 6 sporadic) and 2 gastrinomas (both from patients of the Men1-family). LOH was determined by comparing the autoradiographic patterns of several markers between the normal tissue and the malignant tissue counterpart. All the affected individuals in the MEN1-family shared one haplotype, not present in the healthy individuals. We searched for mutations at the MEN1 gene (SSCP-analysis) in several affected members. An SSCP-mobility shift was found at exon 9, and direct sequencing showed that this corresponded to a common polymorphism at codon 418 (GAC/GAT), LOH, a genetic alteration characteristic of genomic regions containing tumor suppressor genes, was found in all the parathyroid tumors, but not in two gastrinomas. SSCP-analysis of the MEN1-exon 9 polymorphism showed that LOH included the MEN1-gene in the informative parathyroid tumors. In conclusion, LOH at 11q is frequent in Menl-parathyroid tumors, either sporadic or familial, and the deletion involves the MEN1-gene. In contrast, the two gastrinomas did not show LOH, indicating the existence of a second mutation other than the MEN1-deletion in these tumors. Our data suggest that the mechanism that drives tumorigenesis in Menl either familial or sporadic, is influenced by the tissue context.
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ranking = 1
keywords = tumorigenesis
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10/10. comparative genomic hybridization studies in tumours from a patient with multiple endocrine neoplasia type 1.

    OBJECTIVE: To identify genetic changes, other than the MEN1 gene, that might be involved in the tumorigenesis and progression of multiple endocrine neoplasia type 1 (MEN1)-related tumours. methods: We used comparative genomic hybridization (CGH) and loss of heterozygosity (LOH) to study tumours from various sites in a patient with MEN1. RESULTS: Gain of genetic material was not found. Frequent losses of genetic material were found in chromosomes 1, 4, 5, 6, 9, 11 and 18. Besides the chromosome 11 where the MEN1 gene is located, the other regions are known to harbour important tumour suppressor genes. CONCLUSIONS: These results suggest the involvement of other cancer-related genes in the tumorigenesis and progression of MEN1 tumours that warrant further investigations.
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ranking = 2
keywords = tumorigenesis
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