PMID- 34647903
OWN - NLM
STAT- MEDLINE
DCOM- 20220414
LR  - 20220414
IS  - 1479-6821 (Electronic)
IS  - 1351-0088 (Print)
IS  - 1351-0088 (Linking)
VI  - 29
IP  - 1
DP  - 2021 Nov 11
TI  - The molecular characteristics of high-grade gastroenteropancreatic neuroendocrine 
      neoplasms.
PG  - 1-14
LID - ERC-21-0152 [pii]
LID - 10.1530/ERC-21-0152 [doi]
AB  - High-grade (HG) gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN) are 
      rare but have a very poor prognosis and represent a severely understudied class 
      of tumours. Molecular data for HG GEP-NEN are limited, and treatment strategies 
      for the carcinoma subgroup (HG GEP-NEC) are extrapolated from small-cell lung 
      cancer (SCLC). After pathological re-evaluation, we analysed DNA from tumours and 
      matched blood samples from 181 HG GEP-NEN patients; 152 neuroendocrine carcinomas 
      (NEC) and 29 neuroendocrine tumours (NET G3). Based on the sequencing of 360 
      cancer-related genes, we assessed mutations and copy number alterations (CNA). 
      For NEC, frequently mutated genes were TP53 (64%), APC (28%), KRAS (22%) and BRAF 
      (20%). RB1 was only mutated in 14%, but CNAs affecting RB1 were seen in 34%. 
      Other frequent copy number losses were ARID1A (35%), ESR1 (25%) and ATM (31%). 
      Frequent amplifications/gains were found in MYC (51%) and KDM5A (45%). While 
      these molecular features had limited similarities with SCLC, we found potentially 
      targetable alterations in 66% of the NEC samples. Mutations and CNA varied 
      according to primary tumour site with BRAF mutations mainly seen in colon (49%), 
      and FBXW7 mutations mainly seen in rectal cancers (25%). Eight out of 152 (5.3%) 
      NEC were microsatellite instable (MSI). NET G3 had frequent mutations in MEN1 
      (21%), ATRX (17%), DAXX, SETD2 and TP53 (each 14%). We show molecular differences 
      in HG GEP-NEN, related to morphological differentiation and site of origin. 
      Limited similarities to SCLC and a high fraction of targetable alterations 
      indicate a high potential for better-personalized treatments.
FAU - Venizelos, Andreas
AU  - Venizelos A
AD  - K.G. Jebsen Center for Genome-Directed Cancer Therapy, Department of Clinical 
      Science, University of Bergen, Bergen, Norway.
AD  - Department of Oncology, Haukeland University Hospital, Bergen, Norway.
FAU - Elvebakken, Hege
AU  - Elvebakken H
AD  - Department of Oncology, Alesund Hospital, More og Romsdal Hospital Trust, 
      Alesund, Norway.
AD  - Department of Clinical and Molecular Medicine, Faculty of Medicine and Health 
      Sciences, Norwegian University of Science and Technology, Trondheim, Norway.
FAU - Perren, Aurel
AU  - Perren A
AD  - Institute of Pathology, University of Bern, Bern, Switzerland.
FAU - Nikolaienko, Oleksii
AU  - Nikolaienko O
AUID- ORCID: 0000-0002-5910-4934
AD  - K.G. Jebsen Center for Genome-Directed Cancer Therapy, Department of Clinical 
      Science, University of Bergen, Bergen, Norway.
AD  - Department of Oncology, Haukeland University Hospital, Bergen, Norway.
FAU - Deng, Wei
AU  - Deng W
AD  - K.G. Jebsen Center for Genome-Directed Cancer Therapy, Department of Clinical 
      Science, University of Bergen, Bergen, Norway.
AD  - Department of Oncology, Haukeland University Hospital, Bergen, Norway.
FAU - Lothe, Inger Marie B
AU  - Lothe IMB
AD  - Department of Pathology, Oslo University Hospital, Oslo, Norway.
FAU - Couvelard, Anne
AU  - Couvelard A
AD  - Department of Pathology, Universite de Paris, Bichat Hospital, AP-HP, Paris, 
      France.
FAU - Hjortland, Geir Olav
AU  - Hjortland GO
AD  - Department of Oncology, Oslo University Hospital, Oslo, Norway.
FAU - Sundlov, Anna
AU  - Sundlov A
AD  - Departmentt of Oncology, Skane University Hospital, Lund, Sweden.
AD  - Department of Medical Radiation Physics, Lund University, Lund, Sweden.
FAU - Svensson, Johanna
AU  - Svensson J
AD  - Department of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden.
FAU - Garresori, Harrish
AU  - Garresori H
AD  - Department of Oncology, Stavanger University Hospital, Stavanger, Norway.
FAU - Kersten, Christian
AU  - Kersten C
AD  - Department of Research, Hospital of Southern Norway, Kristiansand, Norway.
FAU - Hofsli, Eva
AU  - Hofsli E
AD  - Department of Clinical and Molecular Medicine, Faculty of Medicine and Health 
      Sciences, Norwegian University of Science and Technology, Trondheim, Norway.
AD  - Department of Oncology, St.Olavs Hospital, Trondheim, Norway.
FAU - Detlefsen, Sonke
AU  - Detlefsen S
AD  - Department of Pathology, Odense University Hospital, Odense, Denmark.
AD  - Department of Clinical Medicine, Faculty of Health Sciences, University of 
      Southern Denmark, Odense, Denmark.
FAU - Krogh, Merete
AU  - Krogh M
AD  - Department of Oncology, Odense University Hospital, Odense, Denmark.
FAU - Sorbye, Halfdan
AU  - Sorbye H
AD  - Department of Oncology, Haukeland University Hospital, Bergen, Norway.
AD  - Department of Clinical Science, University of Bergen, Bergen, Norway.
FAU - Knappskog, Stian
AU  - Knappskog S
AD  - K.G. Jebsen Center for Genome-Directed Cancer Therapy, Department of Clinical 
      Science, University of Bergen, Bergen, Norway.
AD  - Department of Oncology, Haukeland University Hospital, Bergen, Norway.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20211111
PL  - England
TA  - Endocr Relat Cancer
JT  - Endocrine-related cancer
JID - 9436481
RN  - EC 1.14.11.- (KDM5A protein, human)
RN  - EC 1.14.11.27 (Retinoblastoma-Binding Protein 2)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins B-raf)
SB  - IM
MH  - *Carcinoma, Neuroendocrine/genetics
MH  - Humans
MH  - *Intestinal Neoplasms/genetics/pathology
MH  - *Neuroendocrine Tumors/genetics/pathology
MH  - *Pancreatic Neoplasms/genetics/pathology
MH  - Proto-Oncogene Proteins B-raf
MH  - Retinoblastoma-Binding Protein 2
MH  - *Stomach Neoplasms/genetics/pathology
PMC - PMC8630776
OTO - NOTNLM
OT  - gastroenteropancreatic
OT  - genetic alterations
OT  - high-grade
OT  - molecular markers
OT  - neuroendocrine carcinoma
OT  - neuroendocrine neoplasms
EDAT- 2021/10/15 06:00
MHDA- 2022/04/15 06:00
PMCR- 2021/11/30
CRDT- 2021/10/14 12:18
PHST- 2021/09/17 00:00 [received]
PHST- 2021/10/14 00:00 [accepted]
PHST- 2021/10/15 06:00 [pubmed]
PHST- 2022/04/15 06:00 [medline]
PHST- 2021/10/14 12:18 [entrez]
PHST- 2021/11/30 00:00 [pmc-release]
AID - ERC-21-0152 [pii]
AID - 10.1530/ERC-21-0152 [doi]
PST - epublish
SO  - Endocr Relat Cancer. 2021 Nov 11;29(1):1-14. doi: 10.1530/ERC-21-0152.