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

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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.

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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

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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).

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  1. Center for Oncological Research (CORE), University of Antwerp and Antwerp University Hospital, Universiteitsplein 1, 2610, Wilrijk, Belgium

    Gitta Boons, Timon Vandamme, Marc Peeters, Guy Van Camp & Ken Op de Beeck

  2. Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Prins Boudewijnlaan 43, 2650, Edegem, Belgium

    Gitta Boons, Timon Vandamme, Guy Van Camp & Ken Op de Beeck

  3. Department of Internal Medicine, Division of Endocrinology, Erasmus Medical Center, Dr. Molewaterplein 50, 3015GE, Rotterdam, The Netherlands

    Timon Vandamme

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  1. Gitta Boons
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Boons, G., Vandamme, T., Peeters, M. et al. Clinical applications of (epi)genetics in gastroenteropancreatic neuroendocrine neoplasms: Moving towards liquid biopsies. Rev Endocr Metab Disord 20, 333–351 (2019). https://doi.org/10.1007/s11154-019-09508-w

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