Driver gene alterations and activated signaling pathways toward malignant progression of gastrointestinal stromal tumors.
Disease Progression
Gastrointestinal Neoplasms
/ genetics
Gastrointestinal Stromal Tumors
/ genetics
Genes, Tumor Suppressor
Humans
Loss of Heterozygosity
Mutation
Oncogenes
Phosphatidylinositol 3-Kinases
/ physiology
Receptor, Platelet-Derived Growth Factor alpha
/ genetics
Signal Transduction
/ physiology
PI3K
driver gene
integrative molecular profiling
malignant GIST
signaling pathway
Journal
Cancer science
ISSN: 1349-7006
Titre abrégé: Cancer Sci
Pays: England
ID NLM: 101168776
Informations de publication
Date de publication:
Dec 2019
Dec 2019
Historique:
received:
24
06
2019
revised:
17
09
2019
accepted:
22
09
2019
pubmed:
26
9
2019
medline:
18
12
2019
entrez:
26
9
2019
Statut:
ppublish
Résumé
Mutually exclusive KIT and PDGFRA mutations are considered to be the earliest events in gastrointestinal stromal tumors (GIST), but insufficient for their malignant progression. Herein, we aimed to identify driver genes and signaling pathways relevant to GIST progression. We investigated genetic profiles of 707 driver genes, including mutations, gene fusions, copy number gain or loss, and gene expression for 65 clinical specimens of surgically dissected GIST, consisting of six metastatic tumors and 59 primary tumors from stomach, small intestine, rectum, and esophagus. Genetic alterations included oncogenic mutations and amplification-dependent expression enhancement for oncogenes (OG), and loss of heterozygosity (LOH) and expression reduction for tumor suppressor genes (TSG). We assigned activated OG and inactivated TSG to 27 signaling pathways, the activation of which was compared between malignant GIST (metastasis and high-risk GIST) and less malignant GIST (low- and very low-risk GIST). Integrative molecular profiling indicated that a greater incidence of genetic alterations of driver genes was detected in malignant GIST (96%, 22 of 23) than in less malignant GIST (73%, 24 of 33). Malignant GIST samples groups showed mutations, LOH, and aberrant expression dominantly in driver genes associated with signaling pathways of PI3K (PIK3CA, AKT1, and PTEN) and the cell cycle (RB1, CDK4, and CDKN1B). Additionally, we identified potential PI3K-related genes, the expression of which was upregulated (SNAI1 and TPX2) or downregulated (BANK1) in malignant GIST. Based on our observations, we propose that inhibition of PI3K pathway signals might potentially be an effective therapeutic strategy against malignant progression of GIST.
Identifiants
pubmed: 31553483
doi: 10.1111/cas.14202
pmc: PMC6890443
doi:
Substances chimiques
Receptor, Platelet-Derived Growth Factor alpha
EC 2.7.10.1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
3821-3833Informations de copyright
© 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.
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