Distinct DNA Methylation Signatures in Neuroendocrine Tumors Specific for Primary Site and Inherited Predisposition.
Adenomatous Polyposis Coli Protein
/ genetics
Adult
Aged
Biopsy
Clinical Trials, Phase II as Topic
CpG Islands
/ genetics
DNA Methylation
Epigenome
Female
Genetic Predisposition to Disease
Humans
Intestine, Small
/ pathology
Male
Middle Aged
Multiple Endocrine Neoplasia Type 1
/ genetics
Neuroendocrine Tumors
/ genetics
Pancreas
/ pathology
Promoter Regions, Genetic
/ genetics
Stomach
/ pathology
von Hippel-Lindau Disease
/ genetics
MEN1
VHL
methylation
neuroendocrine tumors
Journal
The Journal of clinical endocrinology and metabolism
ISSN: 1945-7197
Titre abrégé: J Clin Endocrinol Metab
Pays: United States
ID NLM: 0375362
Informations de publication
Date de publication:
01 10 2020
01 10 2020
Historique:
received:
15
04
2020
accepted:
17
07
2020
pubmed:
25
7
2020
medline:
20
2
2021
entrez:
25
7
2020
Statut:
ppublish
Résumé
To compare the deoxyribonucleic acid (DNA) methylation signature of neuroendocrine tumors (NETs) by primary tumor site and inherited predisposition syndromes von Hippel-Lindau disease (VHL) and multiple endocrine neoplasia type 1 (MEN1). Genome-wide DNA methylation (835 424 CpGs) of 96 NET samples. Principal components analysis (PCA) and unsupervised hierarchical clustering analyses were used to determine DNA methylome signatures. Hypomethylated CpGs were significantly more common in VHL-related versus sporadic and MEN1-related NETs (P < .001 for both comparisons). Small-intestinal NETs (SINETs) had the most differentially methylated CpGs, either hyper- or hypomethylated, followed by duodenal NETs (DNETs) and pancreatic NETs (PNETs, P < .001 for all comparisons). There was complete separation of SINETs on PCA, and 3 NETs of unknown origin clustered with the SINET samples. Sporadic, VHL-related, and MEN1-related PNETs formed distinct groups on PCA, and VHL clustered separately, showing pronounced DNA hypomethylation, while sporadic and MEN1-related NETs clustered together. MEN1-related PNETs, DNETs, and gastric NETs each had a distinct DNA methylome signature, with complete separation by PCA and unsupervised clustering. Finally, we identified 12 hypermethylated CpGs in the 1A promoter of the APC (adenomatous polyposis coli) gene, with higher methylation levels in MEN1-related NETs versus VHL-related and sporadic NETs (P < .001 for both comparisons). DNA CpG methylation profiles are unique in different primary NET types even when occurring in MEN1-related NETs. This tumor DNA methylome signature may be utilized for noninvasive molecular characterization of NETs, through DNA methylation profiling of biopsy samples or even circulating tumor DNA in the near future.
Identifiants
pubmed: 32706863
pii: 5876017
doi: 10.1210/clinem/dgaa477
pmc: PMC7456345
pii:
doi:
Substances chimiques
APC protein, human
0
Adenomatous Polyposis Coli Protein
0
Types de publication
Comparative Study
Journal Article
Research Support, N.I.H., Intramural
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
Published by Oxford University Press on behalf of the Endocrine Society 2020.
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