Genetic analysis of parathyroid and pancreatic tumors in a patient with multiple endocrine neoplasia type 1 using whole-exome sequencing

Kim, Bo Young; Park, Mi-Hyun; Woo, Hae Mi; Jo, Hye Yeong; Kim, Ji Hoon; Choi, Hyung Jin; Koo, Soo Kyung

doi:10.1186/s12881-017-0465-9

Cited by 9 publications

(3 citation statements)

References 20 publications

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“…That chromosome 11 is important for parathyroid pathobiology is already known because the MEN1 gene is located at 11q13 and MEN1 inactivating mutations or loss of heterozygosis at chromosome 11 are the most frequent genomic alteration in PAds. (34) In line with this, we show that chr11-LOH categorizes PAds into two different lncRNA expression classes and MEN1-silencing in PAds-derived cultures increases NEAT1, BC200, HOXA3as, SNHG6, HAR1B, and ZFAS1 lncRNA expression. This observation is confirmed in primary PAd tissues, where tumors with MEN1 gene loss show a general increase of the expression of lncRNAs.…”

Section: Discussionsupporting

confidence: 82%

The Oncosuppressors MEN1 and CDC73 Are Involved in lncRNA Deregulation in Human Parathyroid Tumors

Morotti

Forno

Verdelli

et al. 2020

Journal of Bone and Mineral Research

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A role for long non‐coding RNAs (lncRNAs) in endocrine cancer pathogenesis is emerging. However, knowledge regarding their expression pattern, correlation with known genetic defects, and clinical implications in parathyroid tumors is still unclear. Here, we profiled 90 known lncRNAs in a first series of normal (PaN = 2), adenomatous (PAd = 12), and carcinomatous (PCa = 4) parathyroid glands and we confirmed deregulation of 11 lncRNAs using an independent cohort of patients (PaN = 4; PAd = 26; PCa = 9). Expression of lncRNAs was correlated with cytogenetic aberrations, status of genes multiple endocrine neoplasia 1 (MEN1) and cell division cycle 73 (CDC73), or clinical features. Globally, lncRNAs discriminate according to tissue histology. BC200 consistently identifies parathyroid cancers from adenomas and atypical adenomas. Loss‐of‐heterozygosity (LOH) at chromosomes 1, 11, 15, 21, and 22 significantly impacts expression of lncRNAs in PAds. Silencing of the key parathyroid gene MEN1 modulates the expression of six lncRNAs in primary PAds‐derived cultures. Analogous levels of lncRNAs are measured in PAds with the mutation in the MEN1 gene compared with PAds with wild‐type MEN1. Similarly, carcinomas with mutated CDC73 differ from PCas with wild‐type protein in terms of expression of lncRNAs. PCas harboring CDC73 mutations overexpress BC200 compared to wild‐type carcinomas. Overall, these findings shed light on deregulation of lncRNAs in human parathyroid tumors and propose that circuits between lncRNAs and the oncosuppressors MEN1 or CDC73 may have a role in parathyroid tumorigenesis as epigenetic modulators. © 2020 American Society for Bone and Mineral Research (ASBMR).

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Section: Discussionsupporting

confidence: 82%

The Oncosuppressors MEN1 and CDC73 Are Involved in lncRNA Deregulation in Human Parathyroid Tumors

Morotti

Forno

Verdelli

et al. 2020

Journal of Bone and Mineral Research

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“…A heterogeneity among tumors even in the same patient, suggesting that different tumor-specific tumorigenic mechanisms may contribute to the pathogenesis of MEN1 tumors. The present study supports the clinical applicability of the WES strategy to research on multiple tumor samples and blood [9,10].…”

Section: Multiple Endocrine Neoplasia Type I (Men-i)supporting

confidence: 82%

Molecular Pathology of Pancreatic Endocrine Tumors

Fave¹,

Merola²,

Capurso³

et al. 2017

Pancreatic Cancer

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“…So far, the few available NGS studies evaluating the MEN1 gene have applied WES or WGS approaches, confirming the presence of occasional somatic MEN1 mutations in several sporadic tumors beyond biallelic MEN1 inactivation in parathyroid tissues from MEN1 patients (35,36,37,38,39). Germline MEN1 mutations were analyzed in three studies using WES, in a large primary hyperparathyroidism family and in five MEN1 cases (38,39,40). Also, a 22 genes tNGS panel including MEN1 was recently applied to investigate somatic mutations in sporadic pancreatic neuroendocrine tumors (41).…”

Section: Introductionmentioning

confidence: 92%

Germline mutation landscape of multiple endocrine neoplasia type 1 using full gene next-generation sequencing

Carvalho¹,

Urtremari²,

Jorge³

et al. 2018

European Journal of Endocrinology

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Background Loss-of-function germline MEN1 gene mutations account for 75–95% of patients with multiple endocrine neoplasia type 1 (MEN1). It has been postulated that mutations in non-coding regions of MEN1 might occur in some of the remaining patients; however, this hypothesis has not yet been fully investigated. Objective To sequence for the entire MEN1 including promoter, exons and introns in a large MEN1 cohort and determine the mutation profile. Methods and patients A target next-generation sequencing (tNGS) assay comprising 7.2 kb of the full MEN1 was developed to investigate germline mutations in 76 unrelated MEN1 probands (49 familial, 27 sporadic). tNGS results were validated by Sanger sequencing (SS), and multiplex ligation-dependent probe amplification (MLPA) assay was applied when no mutations were identifiable by both tNGS and SS. Results Germline MEN1 variants were verified in coding region and splicing sites of 57/76 patients (74%) by both tNGS and SS (100% reproducibility). Thirty-eight different pathogenic or likely pathogenic variants were identified, including 13 new and six recurrent variants. Three large deletions were detected by MLPA only. No mutation was detected in 16 patients. In untranslated, regulatory or in deep intronic MEN1 regions of the 76 MEN1 cases, no point or short indel pathogenic variants were found in untranslated, although 33 benign/likely benign and three new VUS variants were detected. Conclusions Our study documents that point or short indel mutations in non-coding regions of MEN1 are very rare events. Also, tNGS proved to be a highly effective technology for routine genetic MEN1 testing.

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Genetic analysis of parathyroid and pancreatic tumors in a patient with multiple endocrine neoplasia type 1 using whole-exome sequencing

Cited by 9 publications

References 20 publications

The Oncosuppressors MEN1 and CDC73 Are Involved in lncRNA Deregulation in Human Parathyroid Tumors

The Oncosuppressors MEN1 and CDC73 Are Involved in lncRNA Deregulation in Human Parathyroid Tumors

Molecular Pathology of Pancreatic Endocrine Tumors

Germline mutation landscape of multiple endocrine neoplasia type 1 using full gene next-generation sequencing

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