Multiple Endocrine Neoplasia Type 1 Syndrome Pancreatic Neuroendocrine Tumor Genotype/Phenotype

Ramamoorthy, Bhavishya; Nilubol, Naris

doi:10.1016/j.soc.2022.10.008

Cited by 3 publications

(4 citation statements)

References 40 publications

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“…It has been suggested that epigenetic mechanisms triggered by environmental factors may influence the disease phenotype in patients carrying the same MEN1 mutation [ 45 , 49 ]. The lack of a direct genotype–phenotype correlation in MEN1 tumorigenesis may be attributed to epigenetic factors acting as cofactors to genetic mutations [ 50 ]. Altered epigenetic regulation of gene expression has been suggested as a potential candidate for novel therapeutic strategies in MEN1 tumorigenesis [ 7 , 13 ].…”

Section: Pancreatic Nets In Men1mentioning

confidence: 99%

“…Several authors have focused on the phenotype–genotype correlations in MEN1 patients, reporting a more aggressive behavior associated with certain genotypes, but no consistent results have been observed [ 7 , 29 , 50 ]. In addition, a recent study found that distant metastases from MEN1-related PanNETs were associated with a higher cumulative methylation index [ 31 ].…”

Section: Pancreatic Nets In Men1mentioning

confidence: 99%

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Hereditary Syndromes Associated with Pancreatic and Lung Neuroendocrine Tumors

Papadopoulou-Marketou,

Tsoli,

Chatzellis

et al. 2024

Cancers

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Pancreatic neuroendocrine tumors (PanNETs) and lung NETs (LNETs) represent a rare but clinically significant subgroup of neoplasms. While the majority is sporadic, approximately 17% of PanNETs and a subset of LNETs develop in the context of monogenic familial tumor syndromes, especially multiple endocrine neoplasia type 1 (MEN1) syndrome. Other inherited syndromes associated with PanNETs include MEN4, von Hippel–Lindau (VHL) syndrome, neurofibromatosis type 1 (NF1), and tuberous sclerosis complex (TSC). These syndromes are highly penetrant and their clinical manifestations may vary even among members of the same family. They are attributed to genetic mutations involving key molecular pathways regulating cell growth, differentiation, and angiogenesis. Pancreatic NETs in hereditary syndromes are often multiple, develop at a younger age compared to sporadic tumors, and are associated with endocrine and nonendocrine tumors derived from multiple organs. Lung NETs are not as common as PanNETs and are mostly encountered in MEN1 syndrome and include typical and atypical lung carcinoids. Early detection of PanNETs and LNETs related to inherited syndromes is crucial, and specific follow-up protocols need to be employed to optimize diagnosis and management. Genetic screening is recommended in childhood, and diagnostic screening starts often in adolescence, even in asymptomatic mutation carriers. Optimal management and therapeutic decisions should be made in the context of a multidisciplinary team in specialized centers, whereas specific biomarkers aiming to identify patients denoted to follow a more aggressive course need to be developed.

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Section: Pancreatic Nets In Men1mentioning

confidence: 99%

Section: Pancreatic Nets In Men1mentioning

confidence: 99%

Hereditary Syndromes Associated with Pancreatic and Lung Neuroendocrine Tumors

Papadopoulou-Marketou,

Tsoli,

Chatzellis

et al. 2024

Cancers

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“…MEN1 (Wermer’s syndrome), an autosomal dominantly inherited syndrome with an increased penetrance, displays a poor genotype/phenotype correlation, a variation that has been hypothesized to be the effect of the “double hit hypothesis” and of a large spectrum of exogenous and endogenous factors (including epigenetic elements such as microRNAs [ 66 ] that were identified in both pancreatic and parathyroid cells) [ 67 , 68 , 69 , 70 , 71 ]. Heterozygote-inactivating pathogenic variants of the MEN1 tumor suppressor gene (chromosome11q13) encoding the MENIN protein are followed by the somatic loss of the heterozygosity of the MEN1 gene at the level of neuroendocrine cells [ 72 , 73 ]. The condition has a familial pattern in nine out of ten cases, while one out of ten subjects with MEN1 shows de novo mutations; thus, the early recognition and prompt introduction of surveillance protocols in this particular instance might not be feasible in daily practice [ 74 , 75 ].…”

Section: Introductionmentioning

confidence: 99%

“…In the meantime, the traditional clinical picture standing for the “three Ps”, namely pituitary, pancreas, and parathyroid NETs, extended toward a heterogonous presentation that also includes more than twenty endocrine and nonendocrine types of tumors like adrenocortical unilateral or bilateral disease (mostly adenomas, and only exceptionally carcinomas [ 79 , 80 ], pheochromocytoma, papillary thyroid carcinoma [ 81 ], and skin tumors such as collagenomas, lipomas/hibernomas, and angiofibromas [ 82 ], as well as cerebral tumors like meninigiomas [ 83 ], different forms of leiomyomas, and lung and thymus tumors [ 84 , 85 , 86 , 87 , 88 ]. MEN1 pathogenic variants in exon 2, 9, and 10 are prone to a more aggressive pancreatic NET behavior [ 72 ]. Other nonendocrine components have been placed in relationship with MEN1 like breast cancer or melanoma, but currently, there is insufficient statistical evidence to directly connect them with the MEN1-associated picture [ 89 , 90 ].…”

Section: Introductionmentioning

confidence: 99%

Turning Points in Cross-Disciplinary Perspective of Primary Hyperparathyroidism and Pancreas Involvements: Hypercalcemia-Induced Pancreatitis, MEN1 Gene-Related Tumors, and Insulin Resistance

Carsote,

Nistor,

Gheorghe

et al. 2024

IJMS

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We aimed to provide an in-depth analysis with respect to three turning points in pancreas involvement in primary hyperparathyroidism (PHP): hypercalcemia-induced pancreatitis (HCa-P), MEN1 (multiple endocrine neoplasia)-related neuroendocrine tumors (NETs), and insulin resistance (IR). This was a comprehensive review conducted via a PubMed search between January 2020 and January 2024. HCa-P (n = 9 studies, N = 1375) involved as a starting point parathyroid NETs (n = 7) or pancreatitis (n = 2, N = 167). Case report-focused analysis (N = 27) showed five cases of pregnancy PHP-HCa-P and three reports of parathyroid carcinoma (female/male ratio of 2/1, ages of 34 in women, men of 56). MEN1-NET studies (n = 7) included MEN1-related insulinomas (n = 2) or MEN1-associated PHP (n = 2) or analyses of genetic profile (n = 3), for a total of 877 MEN1 subjects. In MEN1 insulinomas (N = 77), the rate of associated PHP was 78%. Recurrence after parathyroidectomy (N = 585 with PHP) was higher after less-than-subtotal versus subtotal parathyroidectomy (68% versus 45%, p < 0.001); re-do surgery was 26% depending on surgery for pancreatic NETs (found in 82% of PHP patients). MEN1 pathogenic variants in exon 10 represented an independent risk factor for PHP recurrence. A single pediatric study in MEN1 (N = 80) revealed the following: a PHP rate of 80% and pancreatic NET rate of 35% and 35 underlying germline MEN1 pathogenic variants (and 3/35 of them were newly detected). The co-occurrence of genetic anomalies included the following: CDC73 gene variant, glucokinase regulatory protein gene pathogenic variant (c.151C>T, p.Arg51*), and CAH-X syndrome. IR/metabolic feature-focused analysis identified (n = 10, N = 1010) a heterogeneous spectrum: approximately one-third of adults might have had prediabetes, almost half displayed some level of IR as reflected by HOMA-IR > 2.6, and serum calcium was positively correlated with HOMA-IR. Vitamin D deficiency was associated with a higher rate of metabolic syndrome (n = 1). Normocalcemic and mildly symptomatic hyperparathyroidism (n = 6, N = 193) was associated with a higher fasting glucose and some improvement after parathyroidectomy. This multilayer pancreas/parathyroid analysis highlighted a complex panel of connections from pathogenic factors, including biochemical, molecular, genetic, and metabolic factors, to a clinical multidisciplinary panel.

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Menin in Cancer

Majer,

Hua,

Katona

2024

Genes

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The protein menin is encoded by the MEN1 gene and primarily serves as a nuclear scaffold protein, regulating gene expression through its interaction with and regulation of chromatin modifiers and transcription factors. While the scope of menin’s functions continues to expand, one area of growing investigation is the role of menin in cancer. Menin is increasingly recognized for its dual function as either a tumor suppressor or a tumor promoter in a highly tumor-dependent and context-specific manner. While menin serves as a suppressor of neuroendocrine tumor growth, as seen in the cancer risk syndrome multiple endocrine neoplasia type 1 (MEN1) syndrome caused by pathogenic germline variants in MEN1, recent data demonstrate that menin also suppresses cholangiocarcinoma, pancreatic ductal adenocarcinoma, gastric adenocarcinoma, lung adenocarcinoma, and melanoma. On the other hand, menin can also serve as a tumor promoter in leukemia, colorectal cancer, ovarian and endometrial cancers, Ewing sarcoma, and gliomas. Moreover, menin can either suppress or promote tumorigenesis in the breast and prostate depending on hormone receptor status and may also have mixed roles in hepatocellular carcinoma. Here, we review the rapidly expanding literature on the role and function of menin across a broad array of different cancer types, outlining tumor-specific differences in menin’s function and mechanism of action, as well as identifying its therapeutic potential and highlighting areas for future investigation.

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Multiple Endocrine Neoplasia Type 1 Syndrome Pancreatic Neuroendocrine Tumor Genotype/Phenotype

Cited by 3 publications

References 40 publications

Hereditary Syndromes Associated with Pancreatic and Lung Neuroendocrine Tumors

Hereditary Syndromes Associated with Pancreatic and Lung Neuroendocrine Tumors

Turning Points in Cross-Disciplinary Perspective of Primary Hyperparathyroidism and Pancreas Involvements: Hypercalcemia-Induced Pancreatitis, MEN1 Gene-Related Tumors, and Insulin Resistance

Menin in Cancer

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