Transcriptional alterations in hereditary and sporadic nonfunctioning pancreatic neuroendocrine tumors according to genotype

Keutgen, Xavier M.; Kumar, Suresh; Gara, Sudheer Kumar; Boufraqech, Myriem; Agarwal, Sunita K.; Hruban, Ralph H.; Nilubol, Naris; Quezado, Martha; Finney, Richard; Cam, Maggie; Kebebew, Electron

doi:10.1002/cncr.31057

Cited by 13 publications

(13 citation statements)

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“…-upregulation of genes related to hypoxia-inducible factor molecules, angiogenesis, epithelial mesenchymal transition and/or metastasis, cell cycle and growth factors and receptors (114), -and hypomethylated CpGs, significantly more common in VHL-related versus sporadic and MEN1-related NETs (115).…”

Section: Vhlmentioning

confidence: 99%

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Phakomatoses and Endocrine Gland Tumors: Noteworthy and (Not so) Rare Associations

Chevalier

Dupuis²,

Jannin

et al. 2021

Front. Endocrinol.

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Phakomatoses encompass a group of rare genetic diseases, such as von Hippel-Lindau syndrome (VHL), neurofibromatosis type 1 (NF1), tuberous sclerosis complex (TSC) and Cowden syndrome (CS). These disorders are due to molecular abnormalities on the RAS-PI3K-Akt-mTOR pathway for NF1, TSC and CS, and to hypoxia sensing for VHL. Phakomatoses share some phenotypic traits such as neurological, ophthalmological and cutaneous features. Patients with these diseases are also predisposed to developing multiple endocrine tissue tumors, e.g., pheochromocytomas/paragangliomas are frequent in VHL and NF1. All forms of phakomatoses except CS may be associated with digestive neuroendocrine tumors. More rarely, thyroid cancer and pituitary or parathyroid adenomas have been reported. These susceptibilities are noteworthy, because their occurrence rate, prognosis and management differ slightly from the sporadic forms. The aim of this review is to summarize current knowledge on endocrine glands tumors associated with VHL, NF1, TSC, and CS, especially neuroendocrine tumors and pheochromocytomas/paragangliomas. We particularly detail recent advances concerning prognosis and management, especially parenchyma-sparing surgery and medical targeted therapies such as mTOR, MEK and HIF-2 α inhibitors, which have shown truly encouraging results.

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Section: Vhlmentioning

confidence: 99%

“…- and hypomethylated CpGs, significantly more common in VHL-related versus sporadic and MEN1-related NETs ( 115 ).…”

Section: Digestive Neuroendocrine Neoplasms In Phakomatosesmentioning

confidence: 99%

Phakomatoses and Endocrine Gland Tumors: Noteworthy and (Not so) Rare Associations

Chevalier

Dupuis²,

Jannin

et al. 2021

Front. Endocrinol.

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“…Gene expression analysis was performed as described previously. 28 Briefly, sample labeling and array hybridization were performed according to the Agilent 1-color microarray-based gene expression analysis protocol (Agilent Technologies). Total RNA from each sample was linearly amplified and labeled.…”

Section: Gene Expression Analysismentioning

confidence: 99%

Distinct genome‐wide methylation patterns in sporadic and hereditary nonfunctioning pancreatic neuroendocrine tumors

Tirosh

Mukherjee

Lack

et al. 2019

Cancer

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BACKGROUND: Aberrant methylation is a known cause of cancer initiation and/or progression. There are scant data on the genome-wide methylation pattern of nonfunctioning pancreatic neuroendocrine tumors (NFPanNETs) and sporadic and hereditary NFPanNETs. METHODS: Thirty-three tissue samples were analyzed: they included samples from sporadic (n = 9), von Hippel-Lindau (VHL)-related (n = 10), and multiple endocrine neoplasia type 1 (MEN1)-related NFPanNETs (n = 10) as well as normal islet cells (n = 4) for comparison. Genome-wide CpG methylation profiling was performed with the Infinium MethylationEPIC BeadChip assay and was analyzed with R-based tools. RESULTS: In unsupervised hierarchical clustering, sporadic and MEN1-related NFPanNETs clustered together, and the VHL group was in a separate cluster. MEN1-related NFPanNETs had a higher rate of hypermethylated CpG sites in comparison with sporadic and VHL-related tumor groups. Differentially methylated region analysis confirmed the higher rate of hypermethylation in MEN1-related tumors. Moreover, in an integrated analysis of gene expression data for the same tumor samples, downregulated gene expression was found in most genes that were hypermethylated. In a CpG island methylator phenotype analysis, 3 genes were identified and confirmed to have downregulated gene expression: secreted frizzle-related protein 5 (SFRP5) in sporadic NFPanNETs and cell division cycle-associated 7-like (CDCA7L) and RNA binding motif 47 (RBM47) in MEN1-related NFPanNETs. CONCLUSIONS: MEN1 NFPanNETs have a higher rate of genome-wide hypermethylation than other NFPanNET subtypes. The similarity between the pathways enriched in a methylation analysis of known genes involved in NFPanNET tumorigenesis suggests a key role for aberrant methylation in the pathogenesis of NFPanNETs.

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“…As MEN1 is also one of the most important driver genes in sporadic pNETs (Jiao et al 2011, Scarpa et al 2017, evidence gained from sporadic pNETs might be applied to MEN1-related pNETs as well. Indeed, cumulative methylation index was found not to be statistically different between MEN1-related and sporadic NF-PNETs (Conemans et al 2018a), the prognostic value of ARX/PDX1 IHC was found to be similar in MEN1related and sporadic nf-PNETs (Cejas et al 2019) and mRNA expression analysis has revealed that a subgroup of sporadic pNETs clustered with MEN1-related pNETs, while others clustered alone (Keutgen et al 2018). All this lends credence to the fact that at least a subgroup of sporadic (NF)-pNETs -those with somatic MEN1 mutations?is biologically comparable to MEN1.…”

Section: Discussionmentioning

confidence: 96%

Prognostic factors for the outcome of nonfunctioning pancreatic neuroendocrine tumors in MEN1: a systematic review of literature

Sadowski

Pieterman

Perrier

et al. 2020

Endocrine-Related Cancer

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Metastatic duodenopancreatic neuro-endocrine tumors (dpNETs) are the most important disease-related cause of death in patients with multiple endocrine neoplasia type 1 (MEN1). Nonfunctioning pNETs (NF-pNETs) are highly prevalent in MEN1 and clinically heterogeneous. Therefore, management is controversial. Data on prognostic factors for risk stratification are limited. This systematic review aims to establish the current state of evidence regarding prognostic factors in MEN1-related NF-pNETs. We systematically searched four databases for studies assessing prognostic value of any factor on NF-pNET progression, development of distant metastases, and/or overall survival. In- and exclusion, critical appraisal and data-extraction were performed independently by two authors according to pre-defined criteria. Thirteen studies (370 unique patients) were included. Prognostic factors investigated were tumor size, timing of surgical resection, WHO grade, methylation, p27/p18 expression by immunohistochemistry (IHC), ARX/PDX1 IHC and alternative lengthening of telomeres. Results were complemented with evidence from studies in MEN1-related pNET for which data could not be separately extracted for NF-pNET and data from sporadic NF-pNET. We found that the most important prognostic factors used in clinical decision making in MEN1-related NF-pNETs are tumor size and grade. NF-pNETs <2 cm may be managed with watchful waiting, while surgical resection is advised for NF-pNETs ≥2 cm. Grade 2 NF-pNETs should be considered high risk. The most promising and MEN1-relevant avenues of prognostic research are multi-analyte circulating biomarkers, tissue-based molecular factors and imaging-based prognostication. Multi-institutional collaboration between clinical, translation and basic scientists with uniform data and biospecimen collection in prospective cohorts should advance the field.

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Transcriptional alterations in hereditary and sporadic nonfunctioning pancreatic neuroendocrine tumors according to genotype

Cited by 13 publications

References 45 publications

Phakomatoses and Endocrine Gland Tumors: Noteworthy and (Not so) Rare Associations

Phakomatoses and Endocrine Gland Tumors: Noteworthy and (Not so) Rare Associations

Distinct genome‐wide methylation patterns in sporadic and hereditary nonfunctioning pancreatic neuroendocrine tumors

Prognostic factors for the outcome of nonfunctioning pancreatic neuroendocrine tumors in MEN1: a systematic review of literature

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