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

Abstract

// Chien-Feng Li 1, 2, 3, 8, * , I-Chieh Chuang 4, 8, * , Ting-Ting Liu 4 , Ko-Chin Chen 5, 8 , Yen-Yang Chen 6 , Fu-Min Fang 7 , Shau-Hsuan Li 6 , Tzu-Ju Chen 1, 8 , Shih-Chen Yu 1 , Jui Lan 4,8 , Hsuan-Ying Huang 4, 8 1 Department of Pathology, Chi-Mei Medical Center, Tainan, Taiwan 2 National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan 3 Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan, Taiwan 4 Department of Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan 5 Department of Pathology, Changhua Christian Hospital, Changhua, Taiwan 6 Division of Oncology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan 7 Department of Radiation Oncology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan 8 Bone and Soft Tissue Study Group, Taiwan Society of Pathology, Taiwan * These authors have contributed equally to this work Correspondence to: Hsuan-Ying Huang, email: a120600310@yahoo.com Keywords: cancer metabolism, lipid metabolism, MGLL, transcriptome, GIST Received: May 02, 2016&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Accepted: June 13, 2016&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Published: June 27, 2016 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 &lt; 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 &le; 0.001). Univariately, MGLL overexpression was strongly predictive of poorer disease-free and overall survival (both p &lt; 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.