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

Lakis, Vanessa; Lawlor, Rita T.; Newell, Felicity; Patch, Ann‐Marie; Mafficini, Andrea; Sadanandam, Anguraj; Koufariotis, Lambros T.; Johnston, Rebecca L.; Leonard, Conrad; Wood, Scott; Rusev, Borislav; Corbo, Vincenzo; Luchini, Claudio; Cingarlini, Sara; Landoni, Luca; Salvia, Roberto; Milella, Michèle; Chang, David K.; Bailey, Peter J.; Jamieson, Nigel B.; Duthie, Fraser; Gingras, Marie‐Claude; Muzny, Donna M.; Wheeler, David A.; Gibbs, Richard A.; Milione, Massimo; Apgi,; ARC-Net,; Pederzoli, Paolo; Samra, Jaswinder S.; Gill, Anthony J.; Johns, Amber; Pearson, John V.; Biankin, Andrew V.; Grimmond, Sean M.; Waddell, Nicola; Nones, Kátia; Scarpa, Aldo

doi:10.1038/s42003-020-01469-0

Cited by 36 publications

(36 citation statements)

References 46 publications

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“…Interestingly, intermediate tumors were associated with the shortest disease-free survival and resembled alpha cells rather than beta cells, as 86% expressed ARX by immunostaining. These findings were confirmed in an independent study of 84 sporadic functional and NF-PanNETs [48]. The majority of copy number variations were found in the subgroup with a high prevalence of ATRX/DAXX and MEN1 mutations.…”

Section: Epigenetic Signatures Of Nf-pannetssupporting

confidence: 64%

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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Section: Epigenetic Signatures Of Nf-pannetssupporting

confidence: 64%

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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“…Of the GEP-NETs, the transcriptome of duodenal neuroendocrine tumours (DNETs) has been the least studied, and it has been assumed that they are similar to other small intestinal carcinoids or pancreatic neuroendocrine tumours (PNETs). [9][10][11][12] In particular, many DNETs are duodenal gastrinomas (DGASTs) primarily due to their relationship with the multiple endocrine neoplasia type 1 (MEN1) syndrome. 13 GEP-NETs are associated with MEN1, an autosomal dominant condition in which a non-functional, germline MEN1 allele renders neuroendocrine cells susceptible to transformation or loss of heterozygosity at the remaining wild-type MEN1 locus.…”

Section: Summary Boxmentioning

confidence: 99%

Genome analysis identifies differences in the transcriptional targets of duodenal versus pancreatic neuroendocrine tumours

Rico

Duan

Pandey

et al. 2021

BMJ Open Gastroenterol

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ObjectiveGastroenteropancreatic 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.AimTo identify the possible derivation of GEP-NETs using genome-wide analyses to distinguish small intestinal neuroendocrine tumours, specifically duodenal gastrinomas (DGASTs), from pancreatic neuroendocrine tumours.DesignWhole exome sequencing and RNA-sequencing were performed on surgically resected GEP-NETs (discovery cohort). RNA transcript profiles available in the Gene Expression Omnibus were analysed using R integrated software (validation cohort). Digital spatial profiling (DSP) was used to analyse paraffin-embedded GEP-NETs. Human duodenal organoids were treated with 5 or 10 ng/mL of tumor necrosis factor alpha (TNFα) prior to qPCR and western blot analysis of neuroendocrine cell specification genes.ResultsBoth the discovery and validation cohorts of small intestinal neuroendocrine tumours induced expression of mesenchymal and calcium signalling pathways coincident with a decrease in intestine-specific genes. In particular, calcium-related, smooth muscle and cytoskeletal genes increased in DGASTs, but did not correlate with MEN1 mutation status. Interleukin 17 (IL-17) and tumor necrosis factor alpha (TNFα) signalling pathways were elevated in the DGAST RNA-sequencing. However, DSP analysis confirmed a paucity of immune cells in DGASTs compared with the adjacent tumour-associated Brunner’s glands. Immunofluorescent analysis showed production of these proinflammatory cytokines and phosphorylated signal transducer and activator of transcription 3 (pSTAT3) by the tumours and stroma. Human duodenal organoids treated with TNFα induced neuroendocrine tumour genes, SYP, CHGA and NKX6.3.ConclusionsStromal–epithelial interactions induce proinflammatory cytokines that promote Brunner’s gland reprogramming.

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“…Метилирование гена MGMT характерно для 40% НЭО ПЖ и может быть использовано в качестве предиктивного маркера ответа на терапию темозоломидом [13].…”

Section: Studing the Prognostic Role Of Oncosuppressor Gene Methylation In Sporadic Highly Differentiated Neuroendocrine Pancreatic Tumorunclassified

Studing the Prognostic Role of Oncosuppressor Gene Methylation in Sporadic Highly Differentiated Neuroendocrine Pancreatic Tumors

Trifanov¹,

Kolesnikov²,

Gvaldin³

et al. 2021

СПНО (MPSE)

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Нейроэндокринные опухоли поджелудочной железы можно назвать самой изученной группой нейроэндокринных неоплазий, однако исследования, направленные на изучение эпигенетических процессов в НЭО, немногочисленны. Тем не менее аберрантное метилирование ДНК играет важную роль в канцерогенезе НЭО ПЖ и предопределяет гетерогенность клинической картины заболевания и его прогноз. Изучение эпигенетических особенностей спорадических и наследственных НЭО ПЖ позволило выявить различные паттерны метилирования ДНК в каждой из групп. Имеющиеся на сегодняшний день данные говорят о том, что функционально активные и функционально неактивные НЭО также характеризуются различным метиляторным фенотипом. Однако исследований, направленных на изучение прогностической роли метилирования генов в нейроэндокринных опухолях поджелудочной железы, не проводилось. В данной статье представлены результаты изучения статуса метилирования 8 генов-онкосупрессоров AHRR, APC1A, DAPK, MGMT, MLH1, P16, RASSF1A, RUNX3 и ретротранспозона LINE1 методом пиросеквенирования в спорадических высокодифференцированных нейроэндокринных опухолях поджелудочной железы. Сопоставление клинических наблюдений с данными об эпигенетическом статусе генома позволило сделать выводы о прогностической роли метилирования выбранных генов. Использование статуса метилирования генов-онкосупрессоров с прогностической целью мы считаем наиболее современным подходом к выбору тактики ведения пациентов и считаем, что данная проблема нуждается в дальнейшем изучении. Ключевые слова: нейроэндокринные опухоли, эпигенетика, паттерны метилирования, прогноз.

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

Cited by 36 publications

References 46 publications

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

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

Genome analysis identifies differences in the transcriptional targets of duodenal versus pancreatic neuroendocrine tumours

Studing the Prognostic Role of Oncosuppressor Gene Methylation in Sporadic Highly Differentiated Neuroendocrine Pancreatic Tumors

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