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BBA Clin. 2015 Nov 10;5:1-15. doi: 10.1016/j.bbacli.2015.11.001. eCollection 2016 Jun.

Glioblastomas with copy number gains in EGFR and RNF139 show increased expressions of carbonic anhydrase genes transformed by ENO1.

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Department of Neurology, Louisiana State University Health Sciences Center-Shreveport, RM. 3-438, 1501 Kings Highway, Shreveport, LA 71130, United States 1(former position).
Department of Neurological Surgery, University of Pittsburgh School of Medicine, United States; 4th Floor, Children's Hospital of Pittsburgh, UPMC, 4129 Penn Avenue, Pittsburgh, PA 15224, United States.
Department of Medicine, Louisiana State University Health, 1501 Kings Highway, Shreveport, LA 71130, United States; The Delta Pathology Group, One Saint Mary Place, Shreveport, LA 71101, United States.
Department of Pathology, Division of Neuropathology, S724.1, Scaife Hall, University of Pittsburgh School of Medicine, 3550 Terrace Street, Pittsburgh, PA 15261, United States.



Prominence of glycolysis in glioblastomas may be non-specific or a feature of oncogene-related subgroups (i.e. amplified EGFR, etc.). Relationships between amplified oncogenes and expressions of metabolic genes associated with glycolysis, directly or indirectly via pH, were therefore investigated.


Using multiplex ligation-dependent probe amplification, copy numbers (CN) of 78 oncogenes were quantified in 24 glioblastomas. Related expressions of metabolic genes encoding lactate dehydrogenases (LDHA, LDHC), carbonic anhydrases (CA3, CA12), monocarboxylate transporters (SLC16A3 or MCT4, SLC16A4 or MCT5), ATP citrate lyase (ACLY), glycogen synthase1 (GYS1), hypoxia inducible factor-1A (HIF1A), and enolase1 (ENO1) were determined in 22 by RT-qPCR. To obtain supra-glycolytic levels and adjust for heterogeneity, concurrent ENO1 expression was used to mathematically transform the expression levels of metabolic genes already normalized with delta-delta crossing threshold methodology.


Positive correlations with EGFR occurred for all metabolic genes. Significant differences (Wilcoxon Rank Sum) for oncogene CN gains in tumors of at least 2.00-fold versus less than 2.00-fold occurred for EGFR with CA3's expression (p < 0.03) and for RNF139 with CA12 (p < 0.004). Increased CN of XIAP associated negatively. Tumors with less than 2.00-fold CN gains differed from those with gains for XIAP with CA12 (p < 0.05). Male gender associated with CA12 (p < 0.05).


Glioblastomas with CN increases in EGFR had elevated CA3 expression. Similarly, tumors with RNF149 CN gains had elevated CA12 expression.


In larger studies, subgroups of glioblastomas may emerge according to oncogene-related effects on glycolysis, such as control of pH via effects on carbonic anhydrases, with prognostic and treatment implications.


Amplified oncogenes; CN, copy number; Carbonic anhydrase; DAPI, diaminephylindole; EGFR; GB, glioblastoma; GOI, gene of interest; Glycolysis; HKG, housekeeping gene; IRES, internal ribosome entry site; MLPA, multiplex ligation-dependent probe amplification; MPNST, malignant peripheral nerve sheath tumor; MTB/GF, metabolic/growth factor; NB, normal brain; REMBRANDT, Repository of Molecular Brain Neoplasia Database; RNF139; RT-qPCR, real time quantitative PCR; SLC, solute carrier; WHO, World Health Organization; XIAP; ddCt, delta-delta crossing threshold

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