Diagnostic and management strategies for pNETs in Von Hippel–Lindau: a systematic review

Ahmad, Saya; Naber, Myrthe; Giles, Rachel H.; Valk, Gerlof D.; Leeuwaarde, Rachel S van

doi:10.1530/erc-20-0469

Cited by 9 publications

(5 citation statements)

References 30 publications

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“…Although germline mutations in these genes have been found in patients with clinically sporadic PNETs, these germline mutations are not always associated with a PNET phenotype. PNETs associated with hereditary tumour syndromes occur most commonly in patients with MEN1 syndrome (~80%), followed by VHL (5–17%) and TSC (4%) ( de Laat et al 2016 , Romanet et al 2019 , Ahmad et al 2021 , Evans et al 2022 b ). Separate from PNETs are poorly differentiated highly aggressive pancreatic neuroendocrine carcinomas (PNECs).…”

Section: Introductionmentioning

confidence: 99%

The role of DNA methylation in human pancreatic neuroendocrine tumours

2023

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Pancreatic neuroendocrine tumours (PNETs) are the second most common pancreatic tumour. However, relatively little is known about their tumourigenic drivers, other than mutations involving the Multiple Endocrine Neoplasia 1 (MEN1), ATRX Chromatin Remodeler (ATRX), and Death Domain Associated Protein (DAXX) genes, which are found in ~ 40% of sporadic PNETs. PNETs have a low mutational burden, thereby suggesting that other factors likely contribute to their development, including epigenetic regulators. One such epigenetic process, DNA methylation, silences gene transcription via 5’methylcytosine (5mC), and this is usually facilitated by DNA methyltransferase enzymes at CpG rich areas around gene promoters. However, 5’hydroxymethylcytosine (5hmC), which is the first epigenetic mark during cytosine demethylation, and opposes the function of 5mC, is associated with gene transcription, although the significance of this remains unknown, as it is indistinguishable from 5mC when conventional bisulfite conversion techniques are solely used. Advances in array-based technologies have facilitated investigation of PNET methylomes and enabled PNETs to be clustered by methylome signatures, which has assisted in prognosis and discovery of new aberrantly regulated genes contributing to tumourigenesis. This review will discuss the biology of DNA methylation, its role in PNET development, and impact on prognostication and discovery of epigenome-targeted therapies.

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Section: Introductionmentioning

confidence: 99%

The role of DNA methylation in human pancreatic neuroendocrine tumours

2023

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“…hormone-producing) Pan-NETs present at an early stage due to tumor-related symptoms and complications, non-functional PanNETs (NF-PanNETs) often remain undetected for years. In addition to sporadic tumors, PanNETs frequently occur in inherited endocrine tumor syndromes, such as multiple endocrine neoplasia type 1 (MEN1) and Von Hippel-Lindau disease [2,3].…”

Section: Introductionmentioning

confidence: 99%

Clinical implications of cell‐of‐origin epigenetic characteristics in non‐functional pancreatic neuroendocrine tumors

Dreijerink

Hackeng

Singhi

et al. 2021

The Journal of Pathology

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Primary non-functional pancreatic neuroendocrine tumors (NF-PanNETs) are a heterogeneous group of neuroendocrine neoplasms that display highly variable clinical behavior. Therefore, NF-PanNETs often present clinical teams with a dilemma: the uncertain metastatic potential of the tumor has to be weighed against the morbidity associated with surgical resection. Thus, rather than utilizing current radiologic thresholds, there is an urgent need for improved prognostic biomarkers. Recent studies aimed at understanding the epigenetic underpinnings of NF-PanNETs have led to the identification of tumor subgroups based on histone modification and DNA methylation patterns. These molecular profiles tend to resemble the cellular origins of PanNETs. Subsequent retrospective analyses have demonstrated that these molecular signatures are of prognostic value and, importantly, may be useful in the preoperative setting. These studies have highlighted that sporadic NF-PanNETs displaying biomarkers associated with disease progression and poor prognosis, such as alternative lengthening of telomeres, inactivating alpha thalassemia/mental retardation X-linked (ATRX) or death domain-associated protein (DAXX) gene mutations, or copy number variations, more often display alpha cell characteristics. Conversely, NF-PanNETs with beta cell characteristics often lack these unfavorable biomarkers. Alternative lengthening of telomeres, transcription factor protein expression, and possibly DNA methylation can be assessed in endoscopic ultrasound-guided tumor biopsies. Prospective studies focusing on cell-of-origin and epigenetic profile-driven decision making prior to surgery are likely to be routinely implemented into clinical practice in the near future.

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“…The most characteristic tumours in VHL are hemangioblastoma of the retina and CSN, clear cell renal carcinoma (RCC), pheochromocytoma, and tumour of the inner ear or pancreas. Hemangioblastomas and RCCs are associated with high morbidity and mortality [2,4]. Of all VHL patients, 10-17% develop pNET [1,3].…”

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confidence: 99%

“…pNET connected with VHL are generally non-functional (rarely cause symptomatic disease) and have metastatic potential, so they should be optimally operated before metastatic spread. Krauss et al reported that significant risk factors of metastatic pNET potential are maximum tumour diameter ≥ 2.8 cm, tumour volume doubling time (≤ 24 months), and the mutation in exon 3especially of codon 161 and 167 [2,4].…”

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confidence: 99%