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

Tirosh, Amit; Mukherjee, Sanjit; Lack, Justin; Gara, Sudheer Kumar; Wang, Xin Wei; Quezado, Martha; Keutgen, Xavier M.; Wu, Xiaolin; Cam, Maggie; Kumar, Suresh; Patel, Dhaval; Nilubol, Naris; Tyagi, Monica; Kebebew, Electron

doi:10.1002/cncr.31930

Cited by 39 publications

(38 citation statements)

References 55 publications

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“…In addition, also other epigenetically regulated processes such as chromatin and chromosome condensation are situated in the top GO categories, which again supports the importance of epigenetic deregulation in PNENs. Platelet-related pathways were also enriched, which has been observed previously by Tirosh et al in familial PNENs [12]. It has been shown that PNEN patients with tumor-associated platelets have a worse prognosis, possibly through modulation of the platelet behavior [38].…”

Section: Discussionsupporting

confidence: 72%

“…Furthermore, high portions of hypermethylated DMPs were found in the gene body (22.5%) and the 5'UTR (22.1%) and gene body methylation has been described to be able to increase the gene expression, for example, of metabolic genes or oncogenes [31]. Gene set enrichment analysis has highlighted the MAPK pathway as a possibly important pathway in PNENs, which has been suggested before based on genetic and epigenetic alterations [9,12,32,33]. Cross-talk between the PI3K/AKT/mTOR pathway and the MAPK pathway has been described in neuroendocrine neoplasms and other cancer types, and dual inhibition of these pathways has been shown to be more effective in in vitro and in vivo neuroendocrine neoplasm models [34][35][36].…”

Section: Discussionmentioning

confidence: 92%

“…As these pathways are important for epigenetic regulation, their frequent inactivation suggests an important role for epigenetic deregulation in PNEN tumorigenesis. So far, however, our understanding of the epigenetic landscape of PNENs remains incomplete, with DNA methylation being the most studied epigenetic feature [10][11][12].…”

Section: Introductionmentioning

confidence: 99%

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PDX1 DNA Methylation Distinguishes Two Subtypes of Pancreatic Neuroendocrine Neoplasms with a Different Prognosis

Boons

Vandamme

Ibrahim

et al. 2020

Cancers

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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 the pancreas, their likely cell-of-origin, remain largely unknown. Recently, two subtypes of PNENs have been described which were linked to cell-of-origin and have a different prognosis. A difference in the expression of the transcription factor PDX1 was one of the key molecular differences. In this study, we performed an exploratory genome-wide DNA methylation analysis using Infinium Methylation EPIC arrays (Illumina) on 26 PNENs and pancreatic islets of five healthy donors. In addition, the methylation profile of the PDX1 region was used to perform subtyping in a global cohort of 83 PNEN, 2 healthy alpha cell and 3 healthy beta cell samples. In our exploratory analysis, we identified 26,759 differentially methylated CpGs and 79 differentially methylated regions. The gene set enrichment analysis highlighted several interesting pathways targeted by altered DNA methylation, including MAPK, platelet-related and immune system-related pathways. Using the PDX1 methylation in 83 PNEN, 2 healthy alpha cell and 3 healthy beta cell samples, two subtypes were identified, subtypes A and B, which were similar to alpha and beta cells, respectively. These subtypes had different clinicopathological characteristics, a different pattern of chromosomal alterations and a different prognosis, with subtype A having a significantly worse prognosis compared with subtype B (HR 0.22 [95% CI: 0.051–0.95], p = 0.043). Hence, this study demonstrates that several cancer-related pathways are differently methylated between PNENs and normal islet cells. In addition, we validated the use of the PDX1 methylation status for the subtyping of PNENs and its prognostic importance.

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Section: Discussionsupporting

confidence: 72%

Section: Discussionmentioning

confidence: 92%

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PDX1 DNA Methylation Distinguishes Two Subtypes of Pancreatic Neuroendocrine Neoplasms with a Different Prognosis

Boons

Vandamme

Ibrahim

et al. 2020

Cancers

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“…DNA hypermethylation has an important role in PanNET tumorigenesis and should be further studied to potentially identify novel therapeutic targets (Conemans et al 2018, Tirosh et al 2019. Additional inquiries included the exploration of possible immunotherapybased interventions to prevent metastases or PanNET.…”

Section: Discussionmentioning

confidence: 99%

HEREDITARY ENDOCRINE TUMOURS: CURRENT STATE-OF-THE-ART AND RESEARCH OPPORTUNITIES: MEN1-related pancreatic NETs: identification of unmet clinical needs and future directives

Pieterman

Sadowski

Maxwell

et al. 2020

Endocrine-Related Cancer

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The PanNET Working Group of the 16th International Multiple Endocrine Neoplasia Workshop (MEN2019) convened in Houston, TX, USA, 27–29 March 2019 to discuss key unmet clinical needs related to PanNET in the context of MEN1, with a special focus on non-functioning (nf)-PanNETs. The participants represented a broad range of medical scientists as well as representatives from patient organizations, pharmaceutical industry and research societies. In a case-based approach, participants addressed early detection, surveillance, prognostic factors and management of localized and advanced disease. For each topic, after a review of current evidence, key unmet clinical needs and future research directives to make meaningful progress for MEN1 patients with nf-PanNETs were identified. International multi-institutional collaboration is needed for adequately sized studies and validation of findings in independent datasets. Collaboration between basic, translational and clinical scientists is paramount to establishing a translational science approach. In addition, bringing clinicians, scientists and patients together improves the prioritization of research goals, assures a patient-centered approach and maximizes patient involvement. It was concluded that collaboration, research infrastructure, methodologic and reporting rigor are essential to any translational science effort. The highest priority for nf-PanNETs in MEN1 syndrome are (1) the development of a data and biospecimen collection architecture that is uniform across all MEN1 centers, (2) unified strategies for diagnosis and follow-up of incident and prevalent nf-PanNETs, (3) non-invasive detection of individual nf-PanNETs that have an increased risk of metastasis, (4) chemoprevention clinical trials driven by basic research studies and (5) therapeutic targets for advanced disease based on biologically plausible mechanisms.

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“…From our study, although some of these genes methylation (such as S0 × 17 and RAP1GAP) was previously reported in MDS [31,32], the majority of them were unknown so far. Interestingly, some of them were reported to be methylated in other blood cancers or solid tumors, such as HOXD11, GBX2, CRMP1, RBM47, NHLRC1, WNT2, TUSC3, NRG1, TSPYL5, CNTFR, NR4A3, PHOX2A, KCNA5, PTGDR, HS3ST2, CLDN7, CPT1C, and NKX2-4 [33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48]. Based on these ndings, we further selected the unreported hypermethylated genes with potential roles involved in MDS progression for further validation.…”

Section: Discussionmentioning

confidence: 99%

Genome-Wide Methylation Sequencing Identifies Progression-Related Epigenetic Drivers in Myelodysplastic Syndromes

Zhou

Zhang²,

Xu³

et al. 2020

Preprint

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Background: The mechanism underlying disease progression of myelodysplastic syndromes (MDS) to acute myeloid leukemia (AML) remains poorly elucidated. Epigenetic alterations are increasingly implicated in the pathogenesis of cancer progression including MDS. However, little studies explored the whole-genome methylation alterations during MDS progression.Methods: We conducted reduced representation bisulfite sequencing in four paired MDS/secondary AML (MDS/sAML) patients and intended to discover methylation-associated epigenetic drivers in MDS progression.Results: In four paired MDS/sAML patients, cases at sAML stage showed significantly increased methylation level when compared with their matched MDS stage. A total of 1090 differentially methylated fragments (DMFs) (441 hypermethylated and 649 hypomethylated) were identified involved in MDS pathogenesis, whereas 103 DMFs (96 hypermethylated and 7 hypomethylated) were identified involved in MDS progression. Further targeted bisulfite sequencing identified aberrant GFRA1, IRX1, NPY, and ZNF300 methylation was frequent events in additional de novo MDS and AML patients, of which only ZNF300 methylation was associated with ZNF300 expression. Moreover, ZNF300 hypermethylation in larger cohorts of de novo MDS and AML patients was further confirmed by real-time quantitative methylation-specific PCR. Clinical studies showed that ZNF300 methylation could act as a potential biomarker helpful for the diagnosis and prognosis in MDS and AML patients. In in vitro experiments, overexpression of ZNF300 exhibited anti-proliferative and pro-apoptotic effects in MDS-derived AML cell line SKM-1.Conclusions: Genome-wide DNA hypermethylation was a frequent event during MDS progression. Among these changes, ZNF300 methylation through the regulation of ZNF300 expression acted as an epigenetic driver in MDS progression. These findings give a theoretical basis for investigating and using the efficacy of DNMT inhibitors in MDS patients against disease progression, and provide new insights for targeted therapy in MDS.

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

Cited by 39 publications

References 55 publications

PDX1 DNA Methylation Distinguishes Two Subtypes of Pancreatic Neuroendocrine Neoplasms with a Different Prognosis

PDX1 DNA Methylation Distinguishes Two Subtypes of Pancreatic Neuroendocrine Neoplasms with a Different Prognosis

HEREDITARY ENDOCRINE TUMOURS: CURRENT STATE-OF-THE-ART AND RESEARCH OPPORTUNITIES: MEN1-related pancreatic NETs: identification of unmet clinical needs and future directives

Genome-Wide Methylation Sequencing Identifies Progression-Related Epigenetic Drivers in Myelodysplastic Syndromes

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