title: Transcriptomic reappraisal identifies MGLL overexpression as an unfavorable prognosticator in primary gastrointestinal stromal tumors.
abstract: The role of deregulated cellular metabolism, particularly lipid metabolism, in gastrointestinal stromal tumors (GISTs) remains unclear. Through data mining of published transcriptomes, we examined lipid metabolism-regulating drivers differentially upregulated in high-risk cases and identified monoglyceride lipase (MGLL) as the top-ranking candidate involved in GIST progression. MGLL expression status was examined in three GIST cell lines and two independent sets of primary localized GISTs. MGLL mRNA abundance and immunoexpression was determined in 70 cases through the QuantiGene assay and H-scoring on whole sections, respectively. H-scoring was extended to another cohort for evaluating MGLL immunoexpression on tissue microarrays, yielding 350 informative cases, with KIT/PDGFRA mutation genotypes noted in 213 of them. Both imatinib-sensitive (GIST882) and -resistant (GIST48 and GIST430) cell lines exhibited increased MGLL expression. MGLL mRNA levels significantly increased from adjacent normal tissue to the non-high-risk group (p = 0.030) and from the non-high-risk group to high-risk GISTs (p = 0.012), and were associated with immunoexpression levels (p < 0.001, r = 0.536). MGLL overexpression was associated with the nongastric location (p = 0.022) and increased size (p = 0.017), and was strongly related to mitosis and risk levels defined by NIH and NCCN criteria (all p ≤ 0.001). Univariately, MGLL overexpression was strongly predictive of poorer disease-free and overall survival (both p < 0.001), which remained prognostically independent for both endpoints, along with higher risk levels. Conclusively, MGLL is a lipid metabolic enzyme causatively implicated in GIST progression given its association with unfavorable clincopathological factors and independent negative prognostic effects.
authors.affiliation: Department of Pathology, Chi-Mei Medical Center, Tainan, Taiwan.|National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.|Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan, Taiwan.|Bone and Soft Tissue Study Group, Taiwan Society of Pathology, Taiwan.
authors.forename: Chien-Feng
authors.initials: CF
authors.lastname: Li
authors.affiliation: Department of Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.|Bone and Soft Tissue Study Group, Taiwan Society of Pathology, Taiwan.
authors.forename: I-Chieh
authors.initials: IC
authors.lastname: Chuang
authors.affiliation: Department of Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: Liu
authors.affiliation: Department of Pathology, Changhua Christian Hospital, Changhua, Taiwan.|Bone and Soft Tissue Study Group, Taiwan Society of Pathology, Taiwan.
authors.forename: Ko-Chin
authors.initials: KC
authors.lastname: Chen
authors.affiliation: Division of Oncology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Yen-Yang
authors.initials: YY
authors.lastname: Chen
authors.affiliation: Department of Radiation Oncology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Fu-Min
authors.initials: FM
authors.lastname: Fang
authors.affiliation: Division of Oncology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Shau-Hsuan
authors.initials: SH
authors.lastname: Li
authors.affiliation: Department of Pathology, Chi-Mei Medical Center, Tainan, Taiwan.|Bone and Soft Tissue Study Group, Taiwan Society of Pathology, Taiwan.
authors.forename: Tzu-Ju
authors.initials: TJ
authors.lastname: Chen
authors.affiliation: Department of Pathology, Chi-Mei Medical Center, Tainan, Taiwan.
authors.forename: Shih-Chen
authors.initials: SC
authors.lastname: Yu
authors.affiliation: Department of Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.|Bone and Soft Tissue Study Group, Taiwan Society of Pathology, Taiwan.
authors.forename: Jui
authors.initials: J
authors.lastname: Lan
authors.affiliation: Department of Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.|Bone and Soft Tissue Study Group, Taiwan Society of Pathology, Taiwan.
authors.forename: Hsuan-Ying
authors.initials: HY
authors.lastname: Huang
mesh_terms: D000328:Adult; D000368:Aged; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000175:diagnosis / Q000378:metabolism / Q000401:mortality; D046152:Gastrointestinal Stromal Tumors / Q000175:diagnosis* / Q000378:metabolism* / Q000401:mortality; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D006801:Humans; D053208:Kaplan-Meier Estimate; D008055:Lipids / Q000737:chemistry; D008297:Male; D008875:Middle Aged; D008938:Mitosis; D008994:Monoacylglycerol Lipases / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D011379:Prognosis; D046888:Tissue Array Analysis; D016896:Treatment Outcome
chemical_list: D008055:Lipids; D008994:Monoacylglycerol Lipases
keywords: GIST; MGLL; cancer metabolism; lipid metabolism; transcriptome