The MEN1 gene and pituitary tumours.

Sporadic multiple endocrine neoplasia type 1 (MEN1) is defined as the occurrence of tumours in two of three main endocrine tissue types: parathyroid, pituitary and pancreaticoduodenal. A prolactinoma variant or Burin variant of MEN1 was found to occur in three large kindreds, with more prolactinomas and fewer gastrinomas than typical MEN1. MEN1 tumours differ from common tumours by showing features from the MEN1 gene (e.g. larger pituitary tumours). They also show various expressions of tumour multiplicity; however, pituitary tumour in MEN1 is usually solitary. Diagnosis in MEN1 carriers during childhood is not directed at cancers but at benign morbid tumours. Morbid prolactinoma occurred at the age of 5 years in one MEN1 individual; hence, this is the earliest age at which to recommend tumour surveillance in carriers. The MEN1 gene shows biallelic inactivation in 30% of some types of common variety endocrine tumours (e.g. parathyroid adenoma, gastrinoma, insulinoma and bronchial carcinoid), but in only 1-5% of common pituitary tumours. Heterozygous knockout of MEN1 in mice provides a robust model of MEN1 and has been found to support further research on anti-angiogenesis therapy for pituitary tumours. The rarity of MEN1 mutations in some MEN1-like states aids the identification of other mutated genes, such as AIP, HRPT2 and p27(Kip1). We present recent clinical and basic findings about the MEN1 gene, particularly concerning hereditary vs. common variety pituitary tumours.

Rare germline mutations in cyclin-dependent kinase inhibitor genes in multiple endocrine neoplasia type 1 and related states.

CONTEXT: Germline mutation in the MEN1 gene is the usual cause of multiple endocrine neoplasia type 1 (MEN1). However, the prevalence of identifiable germline MEN1 mutations in familial MEN1 cases is only 70%. Some cases may have a germline mutation in another gene such as the p27 cyclin-dependent kinase inhibitor (CDKI). OBJECTIVE: The aim of the study was to investigate cases of MEN1 or related states for germline mutations in all CDKI genes. METHODS: A total of 196 consecutive index cases were selected with clear or suspected MEN1 and no identifiable germline MEN1 mutation. Every case was analyzed for germline mutation in each of the seven CDKI genes. RESULTS: We identified benign polymorphisms of the CDKI genes and also 15 other initially unclassified sequence variants. After detailed gene/protein analysis, seven of these 15 variants were classified as probably pathological mutations. Three of these seven were probable mutations of p27. The remaining four were probable pathological mutations in three of the other CDKI genes, thereby implicating these three genes in the germline of human tumors. The identification rates for probably pathological mutations among the 196 index cases were similarly low for each of four CDKI genes: p15 (1%), p18 (0.5%), p21 (0.5%), and p27 (1.5%). No characteristic clinical subtype related to MEN1 was identified among the seven index cases and their families. CONCLUSION: Rare germline mutation in any among four (p15, p18, p21, and p27) of the seven CDKIs is a probable cause of MEN1 or of some related states.

Parathyroid tumor development involves deregulation of homeobox genes.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant syndrome caused by mutations in the MEN1 tumor suppressor gene. Loss of the functional second copy of the MEN1 gene causes individuals to develop multiple endocrine tumors, primarily affecting the parathyroid, pituitary, and pancreas. While it is clear that the protein encoded by MEN1, menin, suppresses endocrine tumors, its biochemical functions and direct downstream targets remain unclear. Recent studies have suggested that menin may act as a scaffold protein to coordinate gene transcription, and that menin is an oncogenic cofactor for homeobox (HOX) gene expression in hematopoietic cancer. The role of HOX genes in adult cell differentiation is still obscure, but growing evidence suggests that they may play important roles in the development of cancer. Therefore, we hypothesized that specific HOX genes were regulated by menin in parathyroid tumor development. Utilizing quantitative TaqMan RT-PCR, we compared expression profiles of the 39 HOX genes in human familial MEN1 (fMEN1) parathyroid tumors and sporadic parathyroid adenomas with normal samples. We identified a large set of 23 HOX genes whose deregulation is specific for fMEN1 parathyroid tumors, and only 5 HOX genes whose misexpression are specific for sporadic parathyroid tumor development. These findings provide the first evidence that loss of the MEN1 tumor suppressor gene is associated with deregulation of specific HOX gene expression in the development of familial human parathyroid tumors. Our results strongly reinforce the idea that abnormal expression of developmental HOX genes can be critical in human cancer progression.

The parathyroid/pituitary variant of multiple endocrine neoplasia type 1 usually has causes other than p27Kip1 mutations.

CONTEXT: One variant of multiple endocrine neoplasia type 1 (MEN1) is defined by sporadic tumors of both the parathyroids and pituitary. The prevalence of identified MEN1 mutations in this variant is lower than in familial MEN1 (7% vs. 90%), suggesting different causes. Recently, one case of this variant had a germline mutation of p27(Kip1)/CDKN1B. OBJECTIVE: The objective was to test p27 in germline DNA from cases with tumors of both the parathyroids and pituitary. DESIGN: Medical record review and sequence analysis in DNA were performed. SETTING: This study involved an inpatient and outpatient referral program for cases of endocrine tumors. PATIENTS: Sixteen index cases had sporadic tumors of two organs, both the parathyroids and the pituitary. There were 18 additional index cases with related features of familial tumors. Five subjects were normal controls. No case had an identified MEN1 mutation. INTERVENTIONS: Clinical status of endocrine tumors was tabulated. Sequencing of germline DNA from index cases and control cases for the p27 gene was performed by PCR. MAIN OUTCOME MEASURES: Endocrine tumor types and their expressions were measured, as were sequence changes in the p27 gene. RESULTS: Tumor features were documented in index cases and families. One p27 germline single nucleotide change was identified. This predicted a silent substitution of Thr142Thr. Furthermore, there was a normal prevalence of heterozygosity for a common p27 polymorphism, making a large p27 deletion unlikely in all or most of these cases. CONCLUSIONS: The MEN1 variant with sporadic parathyroid tumors, sporadic pituitary tumor, and no identified MEN1 mutation is usually not caused by p27 germline mutations. It is usually caused by as yet unknown process(es).