Research Papers:

Glyoxalase 1 copy number variation in patients with well differentiated gastro-entero-pancreatic neuroendocrine tumours (GEP-NET)

Mingzhan Xue, Alaa Shafie, Talha Qaiser, Nasir M. Rajpoot, Gregory Kaltsas, Sean James, Kishore Gopalakrishnan, Adrian Fisk, Georgios K. Dimitriadis, Dimitris K. Grammatopoulos, Naila Rabbani, Paul J. Thornalley and Martin O. Weickert _

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Oncotarget. 2017; 8:76961-76973. https://doi.org/10.18632/oncotarget.20290

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Mingzhan Xue1, Alaa Shafie1,2, Talha Qaiser3, Nasir M. Rajpoot3, Gregory Kaltsas4, Sean James4, Kishore Gopalakrishnan4, Adrian Fisk4, Georgios K. Dimitriadis1,4,6, Dimitris K. Grammatopoulos1,4, Naila Rabbani1,5, Paul J. Thornalley1,5,* and Martin O. Weickert1,4,6,*

1Division of Translational Medicine, Clinical Sciences Research Laboratories, Warwick Medical School, University of Warwick, University Hospital, Coventry, U.K.

2Faculty of Applied Medical Sciences, Taif University, Taif, Kingdom of Saudi Arabia

3Department of Computer Sciences, University of Warwick, Coventry, U.K.

4University Hospitals Coventry & Warwickshire NHS Trust, The ARDEN NET Centre, ENETS CoE, Coventry, U.K.

5Warwick Systems Biology Centre, Senate House, University of Warwick, Coventry, U.K.

6Coventry University, Centre for Applied Biological & Exercise Sciences, Coventry, U.K.

*Joint corresponding author

Correspondence to:

Martin O. Weickert, email: [email protected]

Keywords: Glyoxalase, multi-drug resistance, glycation, copy number variation, gastro-entero-pancreatic neuroendocrine tumour

Received: October 11, 2016     Accepted: June 27, 2017     Published: August 16, 2017


Background: The 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.

Methods: GLO1 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.

Results: In 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.

Conclusions: GLO1 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.

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