DNA methylation patterns identify subgroups of pancreatic neuroendocrine tumors with clinical association.

Published on Feb 3, 2021
· DOI :10.1038/S42003-020-01469-0
Vanessa Lakis4
Estimated H-index: 4
(QIMR: QIMR Berghofer Medical Research Institute),
Rita T. Lawlor33
Estimated H-index: 33
+ 35 AuthorsScott Wood20
Estimated H-index: 20
(QIMR: QIMR Berghofer Medical Research Institute)
Here we report the DNA methylation profile of 84 sporadic pancreatic neuroendocrine tumors (PanNETs) with associated clinical and genomic information. We identified three subgroups of PanNETs, termed T1, T2 and T3, with distinct patterns of methylation. The T1 subgroup was enriched for functional tumors and ATRX, DAXX and MEN1 wild-type genotypes. The T2 subgroup contained tumors with mutations in ATRX, DAXX and MEN1 and recurrent patterns of chromosomal losses in half of the genome with no association between regions with recurrent loss and methylation levels. T2 tumors were larger and had lower methylation in the MGMT gene body, which showed positive correlation with gene expression. The T3 subgroup harboured mutations in MEN1 with recurrent loss of chromosome 11, was enriched for grade G1 tumors and showed histological parameters associated with better prognosis. Our results suggest a role for methylation in both driving tumorigenesis and potentially stratifying prognosis in PanNETs.
#1Annunziata Di Domenico (University of Bern)H-Index: 3
Last. Ilaria Marinoni (University of Bern)H-Index: 16
view all 10 authors...
Recent data suggest that Pancreatic Neuroendocrine Tumours (PanNETs) originate from α- or β-cells of the islets of Langerhans. The majority of PanNETs are non-functional and do not express cell-type specific hormones. In the current study we examine whether tumour DNA methylation (DNAme) profiling combined with genomic data is able to identify cell of origin and to reveal pathways involved in PanNET progression. We analyse genome-wide DNAme data of 125 PanNETs and sorted α- and β-cells. To confi...
#1Tincy Simon (Charité)H-Index: 3
#2Soulafa Mamlouk (Charité)H-Index: 8
Last. Christine Sers (Charité)H-Index: 40
view all 23 authors...
Pancreatic Neuroendocrine Neoplasms (PanNENs) comprise a rare and heterogeneous group of tumors derived from neuroendocrine cells of the pancreas. Despite genetic and epigenetic characterization, biomarkers for improved patient stratification and personalized therapy are sparse and targeted therapies, including the mTOR inhibitor Everolimus, have shown limited success. To better define PanNENs tumors we performed multi-omic analyses on 59 tumors with varying grades (NET G1, NET G2, NET G3 and NE...
#9Marian Peeters (University of Antwerp)H-Index: 4
DNA methylation is a crucial epigenetic mechanism for gene expression regulation and cell differentiation. Furthermore, it was found to play a major role in multiple pathological processes, including cancer. In pancreatic neuroendocrine neoplasms (PNENs), epigenetic deregulation is also considered to be of significance, as the most frequently mutated genes have an important function in epigenetic regulation. However, the exact changes in DNA methylation between PNENs and the endocrine cells of t...
#1Antonio Pea (JHUSOM: Johns Hopkins University School of Medicine)H-Index: 22
#2Jun Yu (JHUSOM: Johns Hopkins University School of Medicine)H-Index: 138
Last. Ammar A. Javed (JHUSOM: Johns Hopkins University School of Medicine)H-Index: 24
view all 25 authors...
Objective: :The aim of this study was to investigate the key molecular alterations in small primary pancreatic neuroendocrine tumors (PanNETs) associated with the development of liver metastases.Background:Well-differentiated PanNETs with small size are typically indolent; however, a limited subset
#2Alison Berner (UCL: University College London)H-Index: 3
Last. Christina ThirlwellH-Index: 26
view all 4 authors...
: Neuroendocrine neoplasms (NENs) are a relatively rare group of heterogeneous tumours originating from neuroendocrine cells found throughout the body. Pancreatic NENs (PanNENs) are the second most common pancreatic malignancy accounting for 1-3% of all neoplasms developing in the pancreas. Despite having a low background mutation rate, driver mutations in MEN1, DAXX/ATRX and mTOR pathway genes (PTEN, TSC1/2) are implicated in disease development and progression. Their increased incidence couple...
#1Hanbaro KimH-Index: 3
#2Ki Byung Song (UOU: University of Ulsan)H-Index: 21
Last. Song Cheol Kim (UOU: University of Ulsan)H-Index: 35
view all 6 authors...
This study aimed to evaluate the evolving trends in clinicopathological features of pancreatic neuroendocrine tumors and to analyze the predictors of recurrence after curative resection. Data collected retrospectively from a single center between January 1990 and December 2017 were analyzed. Patients were categorized chronologically into three groups for evolving time-trend analysis. Overall, 542 patients (300 female, 55.4%) underwent surgical resection for pancreatic neuroendocrine tumors, incl...
#1Paloma CejasH-Index: 36
#2Yotam Drier (Broad Institute)H-Index: 25
Last. Ramesh A. Shivdasani (Harvard University)H-Index: 88
view all 27 authors...
Most pancreatic neuroendocrine tumors (PNETs) do not produce excess hormones and are therefore considered ‘non-functional’1–3. As clinical behaviors vary widely and distant metastases are eventually lethal2,4, biological classifications might guide treatment. Using enhancer maps to infer gene regulatory programs, we find that non-functional PNETs fall into two major subtypes, with epigenomes and transcriptomes that partially resemble islet α- and β-cells. Transcription factors ARX and PDX1 speci...
#1Amit Tirosh (NIH: National Institutes of Health)H-Index: 18
#2Sanjit Mukherjee (NIH: National Institutes of Health)H-Index: 12
Last. Electron Kebebew (Stanford University)H-Index: 68
view all 14 authors...
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 =...
Abstract Introduction Neuroendocrine tumors (NETs) are rare, but their incidence is rising. Alkylating agents (ALKY), temozolomide and streptozotocin, are the main chemotherapies used for advanced pancreatic NETs. According to retrospective data, O6-methylguanine-DNA methyltransferase (MGMT) status appears to be a predictive factor of the response to ALKY. Aims The main objective is to evaluate the value of tumor MGMT promoter (pMGMT) methylation in the prediction of the objective response (OR) ...
: Gastroenteropancreatic (GEP) neuroendocrine neoplasms (NENs) are heterogeneous regarding site of origin, biological behavior, and malignant potential. There has been a rapid increase in data publication during the last 10 years, mainly driven by high-throughput studies on pancreatic and small intestinal neuroendocrine tumors (NETs). This review summarizes the present knowledge on genetic and epigenetic alterations. We integrated the available information from each compartment to give a pathway...
Cited By9
#1Krzysztof Szymoński (Jagiellonian University Medical College)
#2Ewelina Lipiec (Jagiellonian University)H-Index: 13
Last. Giovanni Birarda (Elettra Sincrotrone Trieste)H-Index: 19
view all 13 authors...
Abstract null null Pancreatic cancer is one of the most aggressive and lethal malignant neoplasms in the world and 5-year survival rate still remains below 10%. Although, there are many reasons for that, one definitely is the lack of early and unique diagnostic tools for pancreatic cancer screening, which somehow correlates with no sufficient knowledge about cancer’s molecular nature. This article aims to prove the concept that an application of molecular spectroscopic methods including FTIR hyp...
#1Karen Rico (UA: University of Arizona)H-Index: 1
#2Suzann Duan (UA: University of Arizona)
Last. David C. Metz (UPenn: University of Pennsylvania)H-Index: 44
view all 11 authors...
Objective null Gastroenteropancreatic neuroendocrine tumours (GEP-NETs) encompass a diverse group of neoplasms that vary in their secretory products and in their location within the gastrointestinal tract. Their prevalence in the USA is increasing among all adult age groups. null Aim null To identify the possible derivation of GEP-NETs using genome-wide analyses to distinguish small intestinal neuroendocrine tumours, specifically duodenal gastrinomas (DGASTs), from pancreatic neuroendocrine tumo...
#1Ming Shi (SDU: Shandong University)
#2Z Y Fan (SDU: Shandong University)
Last. Hanxiang Zhan (SDU: Shandong University)H-Index: 12
view all 9 authors...
According to the 2019 WHO pathology grading system, high-grade gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) can be divided into well differentiated neuroendocrine tumors G3 (NETs G3) and poorly differentiated neuroendocrine carcinomas (NECs). GEP-NETs G3 and GEP-NECs present significant differences in driver genes and disease origin. NETs G3 and NECs have been confirmed to be two distinct diseases with different genetic backgrounds, however, this issue remains controversial. The pr...
#1Lorenza Pastorino (UniGe: University of Genoa)H-Index: 26
#2Federica GrilloH-Index: 24
Last. William BrunoH-Index: 21
view all 5 authors...
Genomic studies have identified some of the most relevant genetic players in Neuroendocrine Neoplasm (NEN) tumorigenesis. However, we are still far from being able to draw a model that encompasses their heterogeneity, elucidates the different biological effects consequent to the identified molecular events, or incorporates extensive knowledge of molecular biomarkers and therapeutic targets. Here, we reviewed recent insights in NEN tumorigenesis from selected basic research studies on animal mode...
Introduction null Well-differentiated pancreatic neuroendocrine tumors (PanNETs) are a heterogeneous group of primary tumors of the endocrine pancreas. Dysregulation of chromatin remodeling, gene expression alteration, global DNA hypomethylation of non-coding regions, DNA hypermethylation and silencing of tumor suppressor gene promoters are frequent epigenetic changes in PanNETs. These changes exert a role in neoplastic transformation and progression. As epigenetic mechanisms, converse to geneti...
#1Tincy Simon (Humboldt University of Berlin)H-Index: 3
#2Pamela Riemer (Humboldt University of Berlin)H-Index: 7
Last. Christine Sers (DKFZ: German Cancer Research Center)H-Index: 40
view all 22 authors...
Pancreatic Neuroendocrine Carcinomas (PanNECs) are high-grade, poorly-differentiated tumors grouped together with Pancreatic Neuroendocrine Tumors (PanNETs) and placed within the Pancreatic Neuroendocrine Neoplasms (PanNENs) WHO tumor classification. Despite recent studies suggesting the endocrine origin of low-grade PanNETs, high-grade PanNEC origin remains unknown. DNA methylation analysis using the Illumina 850K beadchip array was conducted on 57 PanNEN samples, including 14 PanNECs. Distinct...
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