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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.

SUBMITTER: Li CF

PROVIDER: S-EPMC5226563 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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

Li Chien-Feng CF Chuang I-Chieh IC Liu Ting-Ting TT Chen Ko-Chin KC Chen Yen-Yang YY Fang Fu-Min FM Li Shau-Hsuan SH Chen Tzu-Ju TJ Yu Shih-Chen SC Lan Jui J Huang Hsuan-Ying HY

Oncotarget 20160801 31

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 ...[more]

PMID: 27366945

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Project description:Gastrointestinal stromal tumors (GIST) are rare mesenchymal smooth muscle sarcomas that can arise anywhere within the gastrointestinal tract. Sporadic mutations within the tyrosine kinase receptors of the interstitial cells of Cajal have been identified as the key molecular step in GIST carcinogenesis. Although many patients are asymptomatic, the most common associated symptoms include: abdominal pain, dyspepsia, gastric outlet obstruction, and anorexia. Rarely, GIST can perforate causing life-threatening hemoperitoneum. Most are ultimately diagnosed on cross-sectional imaging studies (i.e., computed tomography and/or magnetic resonance imaging in combination with upper endoscopy. Endoscopic ultrasonographic localization of these tumors within the smooth muscle layer and acquisition of neoplastic spindle cells harboring mutations in the c-KIT gene is pathognomonic. Curative treatment requires a complete gross resection of the tumor. Both open and minimally invasive operations have been shown to reduce recurrence rates and improve long-term survival. While there is considerable debate over whether GIST can be benign neoplasms, we believe that all GIST have malignant potential, but vary in their propensity to recur after resection and metastasize to distant organ sites. Prognostic factors include location, size (i.e., > 5 cm), grade (> 5-10 mitoses per 50 high power fields and specific mutational events that are still being defined. Adjuvant therapy with tyrosine kinase inhibitors, such as imatinib mesylate, has been shown to reduce the risk of recurrence after one year of therapy. Treatment of locally-advanced or borderline resectable gastric GIST with neoadjuvant imatinib has been shown to induce regression in a minority of patients and stabilization in the majority of cases. This treatment strategy potentially reduces the need for more extensive surgical resections and increases the number of patients eligible for curative therapy. The modern surgical treatment of gastric GIST combines the novel use of targeted therapy and aggressive minimally invasive surgical procedures to provide effective treatment for this lethal, but rare gastrointestinal malignancy.

Project description:UnlabelledSummaryGastrointestinal stromal tumors (GISTs) represent 20%-40% of human sarcomas. Although approximately half of GISTs are cured by surgery, prognosis of advanced disease used to be poor due to the high resistance of these tumors to conventional chemo- and radiotherapy. The introduction of molecularly targeted therapy (e.g., with imatinib mesylate) following the discovery of the role of oncogenic mutations in the receptor tyrosine kinases KIT and platelet-derived growth factor α (PDGFRA) significantly increased patient survival. However, GIST cells persist in 95%-97% of imatinib-treated patients who eventually progress and die of the disease because of the emergence of clones with drug-resistant mutations. Because these secondary mutations are highly heterogeneous, even second- and third-line drugs that are effective against certain genotypes have only moderately increased progression-free survival. Consequently, alternative strategies such as targeting molecular mechanisms underlying disease persistence should be considered. We reviewed recently discovered cell-autonomous and microenvironmental mechanisms that could promote the survival of GIST cells in the presence of tyrosine kinase inhibitor therapy. We particularly focused on the potential role of adult precursors for interstitial cells of Cajal (ICCs), the normal counterpart of GISTs. ICC precursors share phenotypic characteristics with cells that emerge in a subset of patients treated with imatinib and in young patients with GIST characterized by loss of succinate dehydrogenase complex proteins and lack of KIT or PDGFRA mutations. Eradication of residual GIST cells and cure of GIST will likely require individualized combinations of several approaches tailored to tumor genotype and phenotype.SignificanceGastrointestinal stromal tumors (GISTs) are one of the most common connective tissue cancers. Most GISTs that cannot be cured by surgery respond to molecularly targeted therapy (e.g., with imatinib); however, tumor cells persist in almost all patients and eventually acquire drug-resistant mutations. Several mechanisms contribute to the survival of GIST cells in the presence of imatinib, including the activation of "escape" mechanisms and the selection of stem-like cells that are not dependent on the expression of the drug targets for survival. Eradication of residual GIST cells and cure of GIST will likely require individualized combinations of several approaches tailored to the genetic makeup and other characteristics of the tumors.

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

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

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