Transcriptomic reappraisal identifies <i>MGLL</i> overexpression as an unfavorable prognosticator in primary gastrointestinal stromal tumors

Li, Chien‐Feng; Chuang, I-Chieh; Liu, Tingting; Chen, Ko–Chin; Chen, Yen‐Yang; Fang, Fu‐Min; Li, Shau-Hsuan; Chen, Tzu‐Ju; Yu, Shih-Chen; Lan, Jui; Huang, Hsuan‐Ying

doi:10.18632/oncotarget.10304

Cited by 14 publications

(14 citation statements)

References 26 publications

(49 reference statements)

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“…MGLL is a serine hydrolase of the AB hydrolase superfamily. Published studies demonstrated that MGLL was correlated with colorectal cancer and gastric cancer [ 32 , 33 ]. In current analyses, we identified that MGLL was correlated with survival and participated multi-pathways in ESCC.…”

Section: Discussionmentioning

confidence: 99%

Microarray analyses reveal genes related to progression and prognosis of esophageal squamous cell carcinoma

et al. 2017

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Esophageal squamous cell carcinoma is a high morbidity and mortality cancer in China. Here are few biomarkers and therapeutic targets. Our study was aimed to identify candidate genes correlated to ESCC. Oncomine, The Cancer Genome Atlas, Gene Expression Omnibus were retrieved for eligible ESCC data. Deregulated genes were identified by meta-analysis and validated by an independent dataset. Survival analyses and bioinformatics analyses were used to explore potential mechanisms. Copy number variant analyses identified upstream mechanisms of candidate genes. In our study, top 200 up/down-regulated genes were identified across two microarrays. A total of 139 different expression genes were validated in GSE53625. Survival analysis found that nine genes were closely related to prognosis. Furthermore, Gene Ontology analyses and Kyoto Encyclopedia of Genes and Genomes analyses showed that different expression genes were mainly enriched in cell division, cell cycle and cell-cell adhesion pathways. Copy number variant analyses indicated that overexpression of ECT2 and other five genes were correlated with copy number amplification. The current study demonstrated that ECT2 and other eight candidate genes were correlated to progression and prognosis of esophageal squamous cell carcinoma, which might provide novel insights to the mechanisms.

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Section: Discussionmentioning

confidence: 99%

Microarray analyses reveal genes related to progression and prognosis of esophageal squamous cell carcinoma

et al. 2017

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“…HSD11B1 mRNA quantification was informative in 70 cases, for which HSD11B1 immunoexpression was assessed on whole tissue sections to correlate between mRNA and protein expression. In a large independent cohort comprising 370 primary GIST samples resected prior to 2009, tissue cores (1.5 mm) in triplicate from each sample were previously assembled into tissue microarrays (TMA) [ 13 , 14 , 18 ], which were recut to perform HSD11B1 -specific fluorescent in situ hybridization (FISH) and HSD11B1 immunohistochemistry. Among these, 213 cases were previously determined for mutations in KIT , PDGFR, and v-raf murine sarcoma viral oncogene homolog B ( BRAF ) [ 13 , 14 ], while 58 cases at various risk levels were subjected to HSD11B1 sequencing in this study.…”

Section: Methodsmentioning

confidence: 99%

“…The clinicopathological characteristics of GISTs in TMA-based analyses and HSD11B1 sequencing were tabulated in Table 1 and Supplementary Table S1 , respectively. The details of GISTs used in HSD11B1 mRNA quantification were previously described [ 14 , 18 ].…”

Section: Methodsmentioning

confidence: 99%

“…A sandwich nucleic acid hybridization method was applied to quantitate the mRNA abundance of housekeeping and target transcripts in the tissue homogenates of formalin-fixed specimens, following the previous protocols [ 14 , 18 , 19 ]. Specific probes that target HSD11B1 transcript were customized to detect its expression by using QuantiGene Multiplex 2.0 assay system (Affymetrix/Panomics, Santa Clara, CA, USA).…”

Section: Methodsmentioning

confidence: 99%

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

Liu

Wang

et al. 2018

JCM

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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.

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“…PDL1 expression was higher in AFIP low-risk samples than in high-risk samples. PDL1 expression was also higher in samples without metastatic 37 • Several lines of observations suggest that KIT/PDGFRA mutational status also impacts on GIST natural course, with most of PDGFRA-mutated GIST showing a more favorable outcome and GIST with a structural variant in the proximal region of KIT exon 11, for example, W557_K558del, or with exon 9 KIT mutation, that is, A502_Y503dup, behaving more aggressively. 38,39 There are other biological factors that are currently used in the diagnosis of GISTs, whose prognostic role could be investigated, since only initial studies have been published at the moment.…”

Section: Biological Markersmentioning

confidence: 99%

Evidence for improvements to risk stratification in high-risk gastrointestinal stromal tumor patients

Greco¹,

Rossi²,

Ruffolo³

et al. 2018

GICTT

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Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. Significant prognostic heterogeneity has been described with GISTs, which can range from clinically benign to frankly malignant tumors. Although several GISTs classification systems have been established to identify tumors with high risk of relapse, there is a sample of patients who still do not receive an appropriate treatment. The classification scores by Fletcher et al and Miettinen and Lasota are the most widely clinically accepted, while the Memorial Sloan Kettering Cancer Center prognostic nomogram is considered the most feasible. There are several studies about new prognostic factors in radiological, biological, and surgical fields. Tumors with mixed growth pattern, enlarged vessels feeding, or draining the mass on computed tomography or with high standardized uptake values on positron emission tomography/ computed tomography should be considered as high-grade GISTs. Among biological markers, the most relevant are programmed cell death ligand 1, Pfetin, SETD2, SLITRK3, mir-215-5p, and monoglyceride lipase. These factors need to be further investigated in order to validate their use in risk stratification. Laparoscopy and open surgery can have the same oncological outcomes even for larger gastric tumors, up to 10 cm. Laparoscopy should be considered the best surgical approach when executed by skilled surgeons and for tumor localized in reachable sites. Adjuvant chemotherapy with imatinib is recommended for high-grade GIST, but the optimal duration of this therapy is still debated. Some authors advocated that imatinib treatment should last for 5 years. A subgroup of GIST is represented by small GISTs, lesions <2 cm in diameter, which need a radical surgical treatment in the presence of symptoms or when high-risk factors such as irregular borders, cystic spaces, ulceration, echogenic foci, internal heterogeneity, tumor progression during follow-up, small intestinal or colorectal localization are present.

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Transcriptomic reappraisal identifies MGLL overexpression as an unfavorable prognosticator in primary gastrointestinal stromal tumors

Cited by 14 publications

References 26 publications

Microarray analyses reveal genes related to progression and prognosis of esophageal squamous cell carcinoma

Microarray analyses reveal genes related to progression and prognosis of esophageal squamous cell carcinoma

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

Evidence for improvements to risk stratification in high-risk gastrointestinal stromal tumor patients

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