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Therefore, NF\u2010PanNETs 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\u2010PanNETs 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\u2010PanNETs displaying biomarkers associated with disease progression and poor prognosis, such as alternative lengthening of telomeres, inactivating alpha thalassemia\/mental retardation X\u2010linked (<jats:italic>ATRX<\/jats:italic>) or death domain\u2010associated protein (<jats:italic>DAXX<\/jats:italic>) gene mutations, or copy number variations, more often display alpha cell characteristics. Conversely, NF\u2010PanNETs 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\u2010guided tumor biopsies. Prospective studies focusing on cell\u2010of\u2010origin and epigenetic profile\u2010driven decision making prior to surgery are likely to be routinely implemented into clinical practice in the near future. \u00a9 2021 The Authors. <jats:italic>The Journal of Pathology<\/jats:italic> published by John Wiley &amp; Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.<\/jats:p>","DOI":"10.1002\/path.5834","type":"journal-article","created":{"date-parts":[[2021,11,9]],"date-time":"2021-11-09T04:49:50Z","timestamp":1636433390000},"page":"143-148","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Clinical implications of cell\u2010of\u2010origin epigenetic characteristics in non\u2010functional pancreatic neuroendocrine tumors"],"prefix":"10.1002","volume":"256","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3140-3502","authenticated-orcid":false,"given":"Koen 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