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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
Article

Abstract

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.

Keywords

Gastroenteropancreatic Neuroendocrine Neoplasms Genetics Epigenetics Biomarkers Liquid Biopsies 

Abbreviations

AUC

Area Under the Curve

CAPTEM

Capecitabine and temozolomide

cfDNA

Cell-free DNA

CgA

Chromogranin A

CIMP

CpG island methylator phenotype

CNV

Copy number variation

CTC

Circulating tumor cell

ctDNA

Circulating tumor DNA

ddPCR

Droplet digital PCR

DFS

Disease-free survival

DSS

Disease-specific survival

EPCAM

Epithelial cell adhesion molecules

FISH

Fluorescence in situ hybridization

G

Grade

GEP-NEN

Gastroenteropancreatic neuroendocrine neoplasm

HIF

Hypoxia inducible factor

IHC

Immunohistochemistry

MEN1/4

Multiple endocrine neoplasia 1/4

miRNA

MicroRNA

MLP

Metastasis-like primary

NEN

Neuroendocrine neoplasm

NF1

Neurofibromatosis Type 1

NGS

Next-generation sequencing

NKA

Neurokinin A

NSE

Neuron-specific Enolase

OS

Overall survival

PD-NEC

Poorly differentiated neuroendocrine carcinoma

PFS

Progression-free survival

PNEC

Pancreatic neuroendocrine carcinoma

PNEN

Pancreatic neuroendocrine neoplasm

PNET

Pancreatic neuroendocrine tumor

PRRT

Peptide receptor radionuclide therapy

PST

Pancreastatin

RFS

Relapse-free survival

siNEN

Small intestinal neuroendocrine neoplasm

SEER

Surveillance, Epidemiology, and End Results program

SSA

Somatostatin analog

SSTR

Somatostatin receptor

TCGA

The Cancer Genome Atlas

TS

Tuberous Sclerosis

VHL

von Hippel Lindau

WD-NET

Well-differentiated neuroendocrine tumor

WES

Whole-exome sequencing

WGS

Whole-genome sequencing

Notes

Acknowledgements

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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