PMID- 33771883
OWN - NLM
STAT- MEDLINE
DCOM- 20220124
LR  - 20220124
IS  - 1557-3125 (Electronic)
IS  - 1541-7786 (Linking)
VI  - 19
IP  - 6
DP  - 2021 Jun
TI  - A Parathyroid-Gut Axis: Hypercalcemia and the Pathogenesis of Gastrinoma in 
      Multiple Endocrine Neoplasia 1.
PG  - 946-949
LID - 10.1158/1541-7786.MCR-21-0073 [doi]
AB  - Patients with multiple endocrine neoplasia 1 (MEN1) syndrome have a germline 
      mutation in the MEN1 gene. Loss of the wild-type allele can initiate endocrine 
      tumorigenesis. Microscopic and macroscopic pituitary, parathyroid, and pancreatic 
      tumors (referred to as the 3 P's) show loss of the wild-type MEN1 allele up to 
      100%. In contrast, the duodenal gastrinoma pathogenesis in MEN1 syndrome follows 
      a hyperplasia-to-neoplasia sequence. Gastrinomas have loss of heterozygosity of 
      the MEN1 locus in <50%, and invariably coincide with linear, diffuse, or 
      micronodular gastrin-cell hyperplasia. The factor initiating the gastrin-cell 
      hyperplasia-to-neoplasia sequence is unknown. In this perspective, we argue that 
      hypercalcemia may promote the gastrin-cell hyperplasia-to-neoplasia sequence 
      through the calcium sensing receptor. Hypercalcemia is present in almost all 
      patients with MEN1 syndrome due to parathyroid adenomas. We propose a 
      parathyroid-gut axis, which could well explain why patients with MEN1 syndrome 
      are regularly cured of duodenal gastrinoma after parathyroid surgery, and might 
      cause MEN1 syndrome phenocopies in MEN1-mutation negative individuals with 
      parathyroid adenomas. This perspective on the pathogenesis of the gastrin-cell 
      hyperplasia and neoplasia sequence sheds new light on tumorigenic mechanisms in 
      neuroendocrine tumors and might open up novel areas of gastrinoma research. It 
      may also shift focus in the treatment of MEN1 syndrome-related gastrinoma to 
      biochemical prevention.
CI  - (c)2021 American Association for Cancer Research.
FAU - Hackeng, Wenzel M
AU  - Hackeng WM
AUID- ORCID: 0000-0001-6795-179X
AD  - Department of Pathology, University Medical Center Utrecht, the Netherlands. 
      wenzelhackeng@gmail.com.
FAU - Dreijerink, Koen M A
AU  - Dreijerink KMA
AUID- ORCID: 0000-0002-3140-3502
AD  - Department of Endocrinology, Amsterdam University Medical Center, the 
      Netherlands.
FAU - Offerhaus, G Johan A
AU  - Offerhaus GJA
AD  - Department of Pathology, University Medical Center Utrecht, the Netherlands.
FAU - Brosens, Lodewijk A A
AU  - Brosens LAA
AUID- ORCID: 0000-0003-1341-8994
AD  - Department of Pathology, University Medical Center Utrecht, the Netherlands.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210326
PL  - United States
TA  - Mol Cancer Res
JT  - Molecular cancer research : MCR
JID - 101150042
RN  - 0 (MEN1 protein, human)
RN  - 0 (Proto-Oncogene Proteins)
SB  - IM
MH  - Alleles
MH  - Duodenum/*metabolism/pathology
MH  - Gastrinoma/*genetics/metabolism/pathology
MH  - Germ-Line Mutation
MH  - Humans
MH  - Hypercalcemia/*genetics/metabolism
MH  - Models, Genetic
MH  - Multiple Endocrine Neoplasia Type 1/*genetics/metabolism/pathology
MH  - Pancreatic Neoplasms/*genetics/metabolism/pathology
MH  - Parathyroid Glands/*metabolism/pathology
MH  - Proto-Oncogene Proteins/genetics/metabolism
MH  - Signal Transduction/genetics
EDAT- 2021/03/28 06:00
MHDA- 2022/01/27 06:00
CRDT- 2021/03/27 05:53
PHST- 2021/01/28 00:00 [received]
PHST- 2021/02/24 00:00 [revised]
PHST- 2021/03/23 00:00 [accepted]
PHST- 2021/03/28 06:00 [pubmed]
PHST- 2022/01/27 06:00 [medline]
PHST- 2021/03/27 05:53 [entrez]
AID - 1541-7786.MCR-21-0073 [pii]
AID - 10.1158/1541-7786.MCR-21-0073 [doi]
PST - ppublish
SO  - Mol Cancer Res. 2021 Jun;19(6):946-949. doi: 10.1158/1541-7786.MCR-21-0073. Epub 
      2021 Mar 26.