Abstract
BackgroundThe glyoxalase-1 gene (GLO1) is a hotspot for copy-number variation (CNV) in human genomes. Increased GLO1 copy-number is associated with multidrug resistance in tumour chemotherapy, but prevalence of GLO1 CNV in gastro-entero-pancreatic neuroendocrine tumours (GEP-NET) is unknown.MethodsGLO1 copy-number variation was measured in 39 patients with GEP-NET (midgut NET, n = 25; pancreatic NET, n = 14) after curative or debulking surgical treatment. Primary tumour tissue, surrounding healthy tissue and, where applicable, additional metastatic tumour tissue were analysed, using real time qPCR. Progression and survival following surgical treatment were monitored over 4.2 ± 0.5 years.ResultsIn the pooled GEP-NET cohort, GLO1 copy-number in healthy tissue was 2.0 in all samples but significantly increased in primary tumour tissue in 43% of patients with pancreatic NET and in 72% of patients with midgut NET, mainly driven by significantly higher GLO1 copy-number in midgut NET. In tissue from additional metastases resection (18 midgut NET and one pancreatic NET), GLO1 copy number was also increased, compared with healthy tissue; but was not significantly different compared with primary tumour tissue. During mean 3 - 5 years follow-up, 8 patients died and 16 patients showed radiological progression. In midgut NET, a high GLO1 copy-number was associated with earlier progression. In NETs with increased GLO1 copy number, there was increased Glo1 protein expression compared to non-malignant tissue.ConclusionsGLO1 copy-number was increased in a large percentage of patients with GEP-NET and correlated positively with increased Glo1 protein in tumour tissue. Analysis of GLO1 copy-number variation particularly in patients with midgut NET could be a novel prognostic marker for tumour progression.
Highlights
Glyoxalase 1 (Glo1) is part of the cytosolic glyoxalase system present in all human cells
glyoxalase-1 gene (GLO1) copy-number was increased in a large percentage of patients with gastroentero-pancreatic neuroendocrine tumours (GEP-NET) and correlated positively with increased Glo1 protein in tumour tissue
In established tumours increased Glo1 expression is a mediator of multidrug resistance (MDR) [8], indicating that MG-mediated cytotoxicity may contribute to the mechanism of action of antitumour agents – possibly by induction of apoptosis and anoikis [9,10,11]
Summary
Glyoxalase 1 (Glo1) is part of the cytosolic glyoxalase system present in all human cells. MG is formed mainly by the low-level spontaneous degradation of triosephosphate intermediates of anaerobic glycolysis [1]. It is a potent glycating agent of protein and DNA, forming mainly the argininederived hydroimidazolone adduct of arginine residues, MG-H1, in proteins; and mainly a mixture of isomeric imidazopurinones, MGdG, of DNA – Figures 1B and 1C [2, 3]. Increased GLO1 copy-number is associated with multidrug resistance in tumour chemotherapy, but prevalence of GLO1 CNV in gastroentero-pancreatic neuroendocrine tumours (GEP-NET) is unknown
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