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J. Clin. Med. 2018, 7(11), 408; https://doi.org/10.3390/jcm7110408

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

1
Department of Pathology, Chi-Mei Medical Center, Tainan 710, Taiwan
2
National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan
3
Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan 710, Taiwan
4
Bone and Soft Tissue Study Group, Taiwan Society of Pathology, Kaohsiung 833, Taiwan
5
Department of Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan
6
Division of Oncology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan
7
Department of Radiation Oncology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan
8
Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
*
Author to whom correspondence should be addressed.
These authors contributed equally to the work.
Received: 8 October 2018 / Revised: 25 October 2018 / Accepted: 29 October 2018 / Published: 1 November 2018
(This article belongs to the Section Molecular Medicine)
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Abstract

The lipid-metabolizing enzymes remain underexplored in gastrointestinal stromal tumors (GISTs). Through transcriptomic reappraisal, hydroxysteroid 11-beta dehydrogenase-1 (HSD11B1) was identified as a top-upregulated, progression-associated gene. To validate the clinical relevance of HSD11B1, the informative results of Sanger sequencing (n = 58), mRNA quantification by branched-chain DNA in situ hybridization assay (n = 70), copy number assay by fluorescent in situ hybridization (n = 350), and immunohistochemistry (n = 350) were correlated with clincopathological variables, KIT/PDGFRA/BRAF genotypes, and disease-free survival (DFS). HSD11B1 was stably silenced to explore its oncogenic function. HSD11B1 mRNA varied between high-risk and non-high-risk groups (p = 0.009) and positively correlated with HSD11B1 immunoexpression (r = 0.783, p < 0.001). HSD11B1 copy-number gain (CNG), including polysomy (5.4%) and amplification (12%), associated with HSD11B1 overexpression (p < 0.001). Predominantly involving the homodimer interface-affecting exon 6 or exon 7, missense HSD11B1 mutations (17.2%) were related to high risk (p = 0.044), age ≥70 years (p = 0.007), and shorter DFS among relapsed cases (p = 0.033). CNG was related to unfavorable KIT/PDGFRA/BRAF genotypes (p = 0.015), while HSD11B1 overexpression was preferential in non-gastric cases (p < 0.001). Both abnormalities strongly associated with risk levels (both p < 0.001) and shorter univariate DFS (both p < 0.0001), and HSD11B1 CNG remained prognostically independent (p < 0.001) with a 3-fold increased hazard ratio. In vitro, HSD11B1 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. View Full-Text
Keywords: gastrointestinal stromal tumor; metabolism; lipid; transcriptome; HSD11B1; gain; mutation; overexpression gastrointestinal stromal tumor; metabolism; lipid; transcriptome; HSD11B1; gain; mutation; overexpression
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Li, C.-F.; Liu, T.-T.; Wang, J.-C.; Yu, S.-C.; Chen, Y.-Y.; Fang, F.-M.; Li, W.-S.; Huang, H.-Y. Hydroxysteroid 11-Beta Dehydrogenase 1 Overexpression with Copy-Number Gain and Missense Mutations in Primary Gastrointestinal Stromal Tumors. J. Clin. Med. 2018, 7, 408.

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