Clinical applications of (epi)genetics in gastroenteropancreatic neuroendocrine neoplasms: Moving towards liquid biopsies

  • Gitta Boons
  • Timon Vandamme
  • Marc Peeters
  • Guy Van CampEmail author
  • Ken Op de Beeck


High-throughput analysis, including next-generation sequencing and microarrays, have strongly improved our understanding of cancer biology. However, genomic data on rare cancer types, such as neuroendocrine neoplasms, has been lagging behind. Neuroendocrine neoplasms (NENs) develop from endocrine cells spread throughout the body and are highly heterogeneous in biological behavior. In this challenging disease, there is an urgent need for new therapies and new diagnostic, prognostic, follow-up and predictive biomarkers to aid patient management. The last decade, molecular data on neuroendocrine neoplasms of the gastrointestinal tract and pancreas, termed gastroenteropancreatic NENs (GEP-NENs), has strongly expanded. The aim of this review is to give an overview of the recent advances on (epi)genetic level and highlight their clinical applications to address the current needs in GEP-NENs. We illustrate how molecular alterations can be and are being used as therapeutic targets, how mutations in DAXX/ATRX and copy number variations could be used as prognostic biomarkers, how far we are in identifying predictive biomarkers and how genetics can contribute to GEP-NEN classification. Finally, we discuss recent studies on liquid biopsies in the field of GEP-NENs and illustrate how liquid biopsies can play a role in patient management. In conclusion, molecular studies have suggested multiple potential biomarkers, but further validation is ongoing.


Gastroenteropancreatic Neuroendocrine Neoplasms Genetics Epigenetics Biomarkers Liquid Biopsies 



Area Under the Curve


Capecitabine and temozolomide


Cell-free DNA


Chromogranin A


CpG island methylator phenotype


Copy number variation


Circulating tumor cell


Circulating tumor DNA


Droplet digital PCR


Disease-free survival


Disease-specific survival


Epithelial cell adhesion molecules


Fluorescence in situ hybridization




Gastroenteropancreatic neuroendocrine neoplasm


Hypoxia inducible factor




Multiple endocrine neoplasia 1/4




Metastasis-like primary


Neuroendocrine neoplasm


Neurofibromatosis Type 1


Next-generation sequencing


Neurokinin A


Neuron-specific Enolase


Overall survival


Poorly differentiated neuroendocrine carcinoma


Progression-free survival


Pancreatic neuroendocrine carcinoma


Pancreatic neuroendocrine neoplasm


Pancreatic neuroendocrine tumor


Peptide receptor radionuclide therapy




Relapse-free survival


Small intestinal neuroendocrine neoplasm


Surveillance, Epidemiology, and End Results program


Somatostatin analog


Somatostatin receptor


The Cancer Genome Atlas


Tuberous Sclerosis


von Hippel Lindau


Well-differentiated neuroendocrine tumor


Whole-exome sequencing


Whole-genome sequencing



This work was funded by ‘Kom op tegen Kanker’ (Stand up to Cancer, the Flemish cancer society) and G. Boons is supported by a Ph.D. fellowship of the Research Foundation – Flanders (FWO; 1195118N).

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

Ethics approval and consent to participate

Not applicable


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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Center for Oncological Research (CORE)University of Antwerp and Antwerp University HospitalWilrijkBelgium
  2. 2.Center of Medical GeneticsUniversity of Antwerp and Antwerp University HospitalEdegemBelgium
  3. 3.Department of Internal Medicine, Division of EndocrinologyErasmus Medical CenterRotterdamThe Netherlands

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