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.
Highlights
Gastrointestinal stromal tumors (GISTs) potentially originate from interstitial Cajal cells or their precursors
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 gastrointestinal stromal tumor (GIST) progression
MGLL mRNA abundance is positively associated with risk levels and protein expression Adopting the same comparative logic in transcriptomic reappraisal, we preselected all 86 GISTs for MGLL mRNA quantification to ensure congruity in the assignment of high-risk versus non-high-risk categories by using both the National Comprehensive Cancer Network (NCCN) and National Institutes of Health (NIH) schemes [9, 10]
Summary
Gastrointestinal stromal tumors (GISTs) potentially originate from interstitial Cajal cells or their precursors. The KIT/PDGFRA genotypes are variably associated with the aggressiveness of resected imatinibnaïve GISTs [3,4,5]; their prognostic value has not been uniformly validated in previous studies [6,7,8]. Both the National Institutes of Health (NIH) and National Comprehensive Cancer Network (NCCN) risk schemes are prognostically useful [9, 10], more accurate prognostication is becoming a critical issue in the postimatinib era for counseling regarding outcomes and for the identification of targetable aberrant molecules other than receptor tyrosine kinases. Identifying candidate deregulated molecules of other signaling pathways is essential for resolving the current limitations in prognostication and therapy
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
