PMID- 32706863
OWN - NLM
STAT- MEDLINE
DCOM- 20210219
LR  - 20211221
IS  - 1945-7197 (Electronic)
IS  - 0021-972X (Print)
IS  - 0021-972X (Linking)
VI  - 105
IP  - 10
DP  - 2020 Oct 1
TI  - Distinct DNA Methylation Signatures in Neuroendocrine Tumors Specific for Primary 
      Site and Inherited Predisposition.
PG  - 3285-94
LID - dgaa477 [pii]
LID - 10.1210/clinem/dgaa477 [doi]
AB  - PURPOSE: 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). METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.
CI  - Published by Oxford University Press on behalf of the Endocrine Society 2020.
FAU - Tirosh, Amit
AU  - Tirosh A
AD  - Endocrine Oncology Bioinformatics Lab and NET Service, Endocrine Institute, Chaim 
      Sheba Medical Centre, Tel Hashomer and Sackler School of Medicine, Tel Aviv 
      University, Tel Aviv, Israel.
AD  - Metabolic Diseases Branch, National Institute of Diabetes and Digestive and 
      Kidney Diseases.
FAU - Killian, Jonathan Keith
AU  - Killian JK
AD  - Genetics, National Cancer Institute, NIH, Bethesda, Maryland.
FAU - Petersen, David
AU  - Petersen D
AD  - Genetics, National Cancer Institute, NIH, Bethesda, Maryland.
FAU - Zhu, Yuelin Jack
AU  - Zhu YJ
AD  - Genetics, National Cancer Institute, NIH, Bethesda, Maryland.
FAU - Walker, Robert L
AU  - Walker RL
AD  - Genetics, National Cancer Institute, NIH, Bethesda, Maryland.
FAU - Blau, Jenny E
AU  - Blau JE
AD  - Metabolic Diseases Branch, National Institute of Diabetes and Digestive and 
      Kidney Diseases.
FAU - Nilubol, Naris
AU  - Nilubol N
AD  - Endocrine Oncology Branches, National Cancer Institute, NIH, Bethesda, Maryland.
FAU - Patel, Dhaval
AU  - Patel D
AD  - Endocrine Oncology Branches, National Cancer Institute, NIH, Bethesda, Maryland.
FAU - Agarwal, Sunita K
AU  - Agarwal SK
AD  - Metabolic Diseases Branch, National Institute of Diabetes and Digestive and 
      Kidney Diseases.
FAU - Weinstein, Lee Scott
AU  - Weinstein LS
AD  - Metabolic Diseases Branch, National Institute of Diabetes and Digestive and 
      Kidney Diseases.
FAU - Meltzer, Paul
AU  - Meltzer P
AD  - Genetics, National Cancer Institute, NIH, Bethesda, Maryland.
FAU - Kebebew, Electron
AU  - Kebebew E
AD  - Department of Surgery and Stanford Cancer Institute, Stanford University, 
      Stanford, California.
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, N.I.H., Intramural
PL  - United States
TA  - J Clin Endocrinol Metab
JT  - The Journal of clinical endocrinology and metabolism
JID - 0375362
RN  - 0 (APC protein, human)
RN  - 0 (Adenomatous Polyposis Coli Protein)
SB  - IM
MH  - Adenomatous Polyposis Coli Protein/genetics
MH  - Adult
MH  - Aged
MH  - Biopsy
MH  - Clinical Trials, Phase II as Topic
MH  - CpG Islands/genetics
MH  - *DNA Methylation
MH  - *Epigenome
MH  - Female
MH  - Genetic Predisposition to Disease
MH  - Humans
MH  - Intestine, Small/pathology
MH  - Male
MH  - Middle Aged
MH  - Multiple Endocrine Neoplasia Type 1/*genetics/pathology
MH  - Neuroendocrine Tumors/*genetics/pathology
MH  - Pancreas/pathology
MH  - Promoter Regions, Genetic/genetics
MH  - Stomach/pathology
MH  - von Hippel-Lindau Disease/*genetics/pathology
PMC - PMC7456345
OTO - NOTNLM
OT  - MEN1
OT  - VHL
OT  - methylation
OT  - neuroendocrine tumors
EDAT- 2020/07/25 06:00
MHDA- 2021/02/20 06:00
PMCR- 2021/07/24
CRDT- 2020/07/25 06:00
PHST- 2020/04/15 00:00 [received]
PHST- 2020/07/17 00:00 [accepted]
PHST- 2020/07/25 06:00 [pubmed]
PHST- 2021/02/20 06:00 [medline]
PHST- 2020/07/25 06:00 [entrez]
PHST- 2021/07/24 00:00 [pmc-release]
AID - 5876017 [pii]
AID - dgaa477 [pii]
AID - 10.1210/clinem/dgaa477 [doi]
PST - ppublish
SO  - J Clin Endocrinol Metab. 2020 Oct 1;105(10):3285-94. doi: 10.1210/clinem/dgaa477.