PMID- 34515662
OWN - NLM
STAT- MEDLINE
DCOM- 20220414
LR  - 20220414
IS  - 1479-6821 (Electronic)
IS  - 1351-0088 (Print)
IS  - 1351-0088 (Linking)
VI  - 28
IP  - 11
DP  - 2021 Oct 4
TI  - Two distinct classes of thymic tumors in patients with MEN1 show LOH at the MEN1 
      locus.
PG  - L15-L19
LID - ERC-21-0226 [pii]
LID - 10.1530/ERC-21-0226 [doi]
AB  - Patients with the multiple endocrine neoplasia type 1 (MEN1) syndrome carry 
      germline heterozygous loss-of-function mutations in the MEN1 gene which 
      predisposes them to develop various endocrine and non-endocrine tumors. Over 90% 
      of the tumors show loss of heterozygosity (LOH) at chromosome 11q13, the MEN1 
      locus, due to somatic loss of the wild-type MEN1 allele. Thymic neuroendocrine 
      tumors (NETs) or thymic carcinoids are uncommon in MEN1 patients but are a major 
      cause of mortality. LOH at the MEN1 locus has not been demonstrated in thymic 
      tumors. The goal of this study was to investigate the molecular aspects of 
      MEN1-associated thymic tumors including LOH at the MEN1 locus and RNA-sequencing 
      (RNA-Seq) to identify genes associated with tumor development and potential 
      targeted therapy. A retrospective chart review of 294 patients with MEN1 germline 
      mutations identified 14 patients (4.8%) with thymic tumors (12 thymic NETs and 2 
      thymomas). LOH at the MEN1 locus was identified in 10 tumors including the 2 
      thymomas, demonstrating that somatic LOH at the MEN1 locus is also the mechanism 
      for thymic tumor development. Unsupervised principal component analysis and 
      hierarchical clustering of RNA-Seq data showed that thymic NETs formed a 
      homogenous transcriptomic group separate from thymoma and normal thymus. KSR2 
      (kinase suppressor of Ras 2), that promotes Ras-mediated signaling, was 
      abundantly expressed in thymic NETs, a potential therapeutic target. The 
      molecular insights gained from our study about thymic tumors combined with 
      similar data from other MEN1-associated tumors may lead to better surveillance 
      and treatment of these rare tumors.
FAU - Mandl, Adel
AU  - Mandl A
AD  - Metabolic Diseases Branch, Metabolic Diseases Branch, National Institute of 
      Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA.
FAU - Welch, James M
AU  - Welch JM
AD  - Metabolic Diseases Branch, Metabolic Diseases Branch, National Institute of 
      Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA.
FAU - Kapoor, Gayathri
AU  - Kapoor G
AD  - Metabolic Diseases Branch, Metabolic Diseases Branch, National Institute of 
      Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA.
FAU - Parekh, Vaishali I
AU  - Parekh VI
AD  - Metabolic Diseases Branch, Metabolic Diseases Branch, National Institute of 
      Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA.
FAU - Schrump, David S
AU  - Schrump DS
AD  - Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, 
      USA.
FAU - Ripley, R Taylor
AU  - Ripley RT
AD  - Division of General Thoracic Surgery, Baylor College of Medicine, Houston, Texas, 
      USA.
FAU - Walter, Mary F
AU  - Walter MF
AD  - NIDDK Clinical Core, National Institute of Diabetes and Digestive and Kidney 
      Diseases, NIH, Bethesda, Maryland, USA.
FAU - Del Rivero, Jaydira
AU  - Del Rivero J
AUID- ORCID: 0000-0001-9710-4030
AD  - Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, 
      USA.
FAU - Jha, Smita
AU  - Jha S
AD  - Metabolic Diseases Branch, Metabolic Diseases Branch, National Institute of 
      Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA.
FAU - Simonds, William F
AU  - Simonds WF
AUID- ORCID: 0000-0001-7806-706X
AD  - Metabolic Diseases Branch, Metabolic Diseases Branch, National Institute of 
      Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA.
FAU - Jensen, Robert T
AU  - Jensen RT
AD  - Digestive Diseases Branch, National Institute of Diabetes and Digestive and 
      Kidney Diseases, NIH, Bethesda, Maryland, USA.
FAU - Weinstein, Lee S
AU  - Weinstein LS
AD  - Metabolic Diseases Branch, Metabolic Diseases Branch, National Institute of 
      Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA.
FAU - Blau, Jenny E
AU  - Blau JE
AD  - Metabolic Diseases Branch, Metabolic Diseases Branch, National Institute of 
      Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA.
FAU - Agarwal, Sunita K
AU  - Agarwal SK
AUID- ORCID: 0000-0002-7557-3191
AD  - Metabolic Diseases Branch, Metabolic Diseases Branch, National Institute of 
      Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA.
LA  - eng
GR  - ZIA DK075085/ImNIH/Intramural NIH HHS/United States
GR  - ZIA BC011115/ImNIH/Intramural NIH HHS/United States
PT  - Letter
PT  - Research Support, N.I.H., Intramural
DEP - 20211004
PL  - England
TA  - Endocr Relat Cancer
JT  - Endocrine-related cancer
JID - 9436481
SB  - IM
MH  - Humans
MH  - Loss of Heterozygosity
MH  - *Multiple Endocrine Neoplasia Type 1/genetics/pathology
MH  - Retrospective Studies
MH  - *Thymoma
MH  - *Thymus Neoplasms/genetics
PMC - PMC8558845
OTO - NOTNLM
OT  - multiple endocrine neoplasia
OT  - neuroendocrine tumor
OT  - thymic carcinoid
OT  - thymoma
OT  - thymus
EDAT- 2021/09/14 06:00
MHDA- 2022/04/15 06:00
PMCR- 2021/11/01
CRDT- 2021/09/13 12:22
PHST- 2021/09/06 00:00 [received]
PHST- 2021/09/10 00:00 [accepted]
PHST- 2021/09/14 06:00 [pubmed]
PHST- 2022/04/15 06:00 [medline]
PHST- 2021/09/13 12:22 [entrez]
PHST- 2021/11/01 00:00 [pmc-release]
AID - ERC-21-0226 [pii]
AID - 10.1530/ERC-21-0226 [doi]
PST - epublish
SO  - Endocr Relat Cancer. 2021 Oct 4;28(11):L15-L19. doi: 10.1530/ERC-21-0226.