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

Abstract

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.

Overview of the 2022 WHO Classification of Neuroendocrine Neoplasms

“…Epigenetic or transcriptomic signatures have been used to classify non-functioning pancreatic NETs based on endocrine cell type differentiation [82][83][84][85][86]. These studies have revealed three epigenetic subtypes (Table 4) resembling A (alpha) or B (beta) cells, enriched for specific structural alterations and mutational profiles, and with prognostic relevance [86]; PDX1 and ARX were found to be useful surrogate immunohistochemical markers to distinguish these tumor subtypes [83]. One group resembles B cells, without copy number alterations, MEN1 or ATRX/DAXX mutations (therefore no resulting alternative lengthening of telomeres (ALT)), and a favorable prognosis.…”

Insights into Epigenetic Changes Related to Genetic Variants and Cells-of-Origin of Pancreatic Neuroendocrine Tumors: An Algorithm for Practical Workup

“…In summary, based on the presented data [ 9 , 19 , 41 , 42 , 44 , 71 , 82 ], at least five groups of PanNENs can be identified as they differ by cell of origin, clinical features, genetic, and epigenetic background ( Table 2 ).…”

“…In addition, these indolent neoplasms differ from the other subgroups in terms of their genetic background [ 9 ]. In contrast, PanNEN 4 resembles more likely to α cells, one theory suggesting that they probably existed as a NF-PanNET before developing functional features [ 42 ]. The last subtype refers to a proliferative group proposed by Kevin Yang et al [ 44 ].…”

“…Another point of interest is the analysis of the cells of origin of these tumor subtypes, which could clarify their unpredictable evolution and potentially facilitate a new target therapy. The majority of studies presented in this review included preponderantly sporadic tumors, with few MEN1-syndrome related NF-PanNETs, although it is not certain if their findings apply to MEN-1 related and other hereditary NF-PanNETs [ 42 ].…”

“…In contrast, typical indolent insulinomas present a different genetic background than NF-PanNETs. Therefore, the genetic and epigenetic features can differentiate between typical indolent insulinomas and aggressive insulinomas [ 41 , 42 ]. In addition, in a recent study, it was shown that ATRX/DAXX/MEN1 (A-D-M) mutated tumors and A-D-M wild type (WT) cluster differently based on DNA methylation and gene expression patterns.…”