Hydroxysteroid 11-Beta Dehydrogenase 1 Overexpression with Copy-Number Gain and Missense Mutations in Primary Gastrointestinal Stromal Tumors.

Chien-Feng Li, Ting-Ting Liu, Jui-Chu Wang, Shih-Chen Yu, Yen-Yang Chen, Fu-Min Fang, Wan-Shan Li, Hsuan-Ying Huang

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Abstract

The lipid-metabolizing enzymes remain underexplored in gastrointestinal stromal tumors (GISTs). Through transcriptomic reappraisal, hydroxysteroid 11-beta dehydrogenase-1 () was identified as a top-upregulated, progression-associated gene. To validate the clinical relevance of , the informative results of Sanger sequencing ( = 58), mRNA quantification by branched-chain DNA in situ hybridization assay ( = 70), copy number assay by fluorescent in situ hybridization ( = 350), and immunohistochemistry ( = 350) were correlated with clincopathological variables, genotypes, and disease-free survival (DFS). was stably silenced to explore its oncogenic function. mRNA varied between high-risk and non-high-risk groups ( = 0.009) and positively correlated with HSD11B1 immunoexpression ( = 0.783, < 0.001). copy-number gain (CNG), including polysomy (5.4%) and amplification (12%), associated with HSD11B1 overexpression ( < 0.001). Predominantly involving the homodimer interface-affecting exon 6 or exon 7, missense mutations (17.2%) were related to high risk ( = 0.044), age ≥70 years ( = 0.007), and shorter DFS among relapsed cases ( = 0.033). CNG was related to unfavorable genotypes ( = 0.015), while HSD11B1 overexpression was preferential in non-gastric cases ( < 0.001). Both abnormalities strongly associated with risk levels (both < 0.001) and shorter univariate DFS (both < 0.0001), and CNG remained prognostically independent ( < 0.001) with a 3-fold increased hazard ratio. In vitro, knockdown significantly inhibited proliferation and caused G2/M arrest. In conclusion, HSD11B1 overexpression may occur owing to CNG, confer a pro-proliferative function, and predict a worse prognosis in GISTs.
Original languageAmerican English
JournalJournal of Clinical Medicine
Volume7
Issue number11
DOIs
StatePublished - 2018

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