PMID- 33186588
OWN - NLM
STAT- MEDLINE
DCOM- 20210719
LR  - 20210719
IS  - 1532-8392 (Electronic)
IS  - 0046-8177 (Linking)
VI  - 107
DP  - 2021 Jan
TI  - Loss of SFRP1 expression is a key progression event in gastrointestinal stromal 
      tumor pathogenesis.
PG  - 69-79
LID - S0046-8177(20)30216-1 [pii]
LID - 10.1016/j.humpath.2020.10.010 [doi]
AB  - The mechanism of high-grade transformation in gastrointestinal stromal tumors 
      (GISTs) remains to be clarified. We aim to discover the key progression events by 
      studying biphasic GISTs. The study group included 101 GISTs. Nineteen of these 
      had been screened from 263 GISTs to represent the early stage of GIST high-grade 
      transformation, characterized by juxtaposed low-grade and high-grade regions in 
      the same tumor (so-called biphasic GISTs). Mutational analyses, fluorescence in 
      situ hybridization (FISH), NanoString analyses, telomere analysis, and gene 
      expression profiling were carried out, followed by in silico analyses, cell line 
      study, and immunohistochemical validation. Using gene expression analysis, 
      downregulation of SFRP1 was revealed to be the main event in GIST high-grade 
      transformation (p = 0.013), accompanied by upregulation of EZH2. In silico 
      analyses revealed that downregulation of SFRP1 was a common feature in GIST 
      progression across several different series. Immunohistochemically, the 
      expression of SFRP1 was validated to be significantly lower in high-grade GISTs 
      (WHO risk group 3a or higher) than in low-grade GISTs (p < 0.001), and 
      attenuation/loss of SFRP1 was associated with GIST tumor progression (p < 0.001). 
      By NanoString and FISH analyses, chromosomal 9/9p loss was the only recurrent 
      large-scale chromosome aberration in biphasic GISTs, with a correlation with 
      SFRP1 downregulation. Subclones containing chromosome 9/9p loss could be 
      appreciated in the low-grade parts of biphasic GISTs. TP53 mutation, RB1 loss, 
      KIT/PDGFRA mutation, and alternative lengthening of telomeres did not play a 
      significant role in GIST high-grade transformation. In conclusion, high-grade 
      transformation of GISTs features SFRP1 downregulation and chromosome 9/9p loss.
CI  - Copyright (c) 2020 Elsevier Inc. All rights reserved.
FAU - Liang, Cher-Wei
AU  - Liang CW
AD  - Department and Graduate Institute of Pathology, National Taiwan University 
      Hospital and National Taiwan University College of Medicine, Taipei, 10002, 
      Taiwan; Department of Pathology, Fu Jen Catholic University Hospital, Fu Jen 
      Catholic University, New Taipei City, 24352, Taiwan; School of Medicine, College 
      of Medicine, Fu Jen Catholic University, New Taipei City, 24205, Taiwan.
FAU - Yang, Ching-Yao
AU  - Yang CY
AD  - Department of Surgery, National Taiwan University Hospital and National Taiwan 
      University College of Medicine, Taipei, 10002, Taiwan.
FAU - Flavin, Richard
AU  - Flavin R
AD  - Department of Pathology, St. James's Hospital and Trinity College Dublin, Dublin, 
      D02, Ireland.
FAU - Fletcher, Jonathan A
AU  - Fletcher JA
AD  - Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, 
      Boston, MA, 02115, USA.
FAU - Lu, Tzu-Pin
AU  - Lu TP
AD  - Department of Public Health, Institute of Epidemiology and Preventive Medicine, 
      National Taiwan University, Taipei, 10055, Taiwan.
FAU - Lai, I-Rue
AU  - Lai IR
AD  - Department of Surgery, National Taiwan University Hospital and National Taiwan 
      University College of Medicine, Taipei, 10002, Taiwan.
FAU - Li, Yu-I
AU  - Li YI
AD  - Department of Pathology, Fu Jen Catholic University Hospital, Fu Jen Catholic 
      University, New Taipei City, 24352, Taiwan.
FAU - Chang, Yih-Leong
AU  - Chang YL
AD  - Department and Graduate Institute of Pathology, National Taiwan University 
      Hospital and National Taiwan University College of Medicine, Taipei, 10002, 
      Taiwan. Electronic address: ntuhylc@gmail.com.
FAU - Lee, Jen-Chieh
AU  - Lee JC
AD  - Department and Graduate Institute of Pathology, National Taiwan University 
      Hospital and National Taiwan University College of Medicine, Taipei, 10002, 
      Taiwan. Electronic address: leejenchieh@ntuh.gov.tw.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20201110
PL  - United States
TA  - Hum Pathol
JT  - Human pathology
JID - 9421547
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (Intercellular Signaling Peptides and Proteins)
RN  - 0 (Membrane Proteins)
RN  - 0 (SFRP1 protein, human)
RN  - EC 2.1.1.43 (EZH2 protein, human)
RN  - EC 2.1.1.43 (Enhancer of Zeste Homolog 2 Protein)
SB  - IM
MH  - Biomarkers, Tumor/metabolism
MH  - Cell Transformation, Neoplastic/genetics/metabolism
MH  - Chromosomes, Human, Pair 9/genetics
MH  - Disease Progression
MH  - Enhancer of Zeste Homolog 2 Protein/metabolism
MH  - Gastrointestinal Stromal Tumors/genetics/metabolism/*pathology
MH  - Humans
MH  - Intercellular Signaling Peptides and Proteins/*metabolism
MH  - Membrane Proteins/*metabolism
OTO - NOTNLM
OT  - CDKN2A
OT  - Gastrointestinal stromal tumor
OT  - NanoString
OT  - SFRP1
OT  - p16(INK4a)
EDAT- 2020/11/14 06:00
MHDA- 2021/07/20 06:00
CRDT- 2020/11/13 20:08
PHST- 2020/08/30 00:00 [received]
PHST- 2020/10/26 00:00 [revised]
PHST- 2020/10/30 00:00 [accepted]
PHST- 2020/11/14 06:00 [pubmed]
PHST- 2021/07/20 06:00 [medline]
PHST- 2020/11/13 20:08 [entrez]
AID - S0046-8177(20)30216-1 [pii]
AID - 10.1016/j.humpath.2020.10.010 [doi]
PST - ppublish
SO  - Hum Pathol. 2021 Jan;107:69-79. doi: 10.1016/j.humpath.2020.10.010. Epub 2020 Nov 
      10.