Genomic copy number alteration of glycolytic pathway in endometrial cancer

Metabolic reprogramming is one of the hallmarks of cancer cells, but very little is known about the difference in the expression of metabolic genes between cancer and normal tissues. The degree to which different cancer types display similar metabolic alteration is poorly understood. The best-known example of metabolic disturbance in cancer cells is the Warburg effect. The Warburg effect is the phenomenon of the cancer cells favoring the anaerobic glycolysis even in the presence of oxygen. It is displayed by most cancer cells. Although the genomic, transcriptomic, and proteomic studies have been published, metalobomic differences are still a major gap in our knowledge. Among women the most common malignancy is endometrial cancer. In this retrospective study, the authors investigated the genomic instability of glycolytic genes in endometrial carcinoma patients using array-based comparative genomic hybridization (aCGH) reports. The results indicate that among 54 patients diagnosed with endometrial carcinoma, in 21 patients, pathogenic genomic instability was detected which are linked with the disease. Among the 21 patients who had genomic instability, 19 of them (90.5%) displayed copy number variations of at least one or more glycolysis genes based on the genomic laboratory reports of the patients.

Copy number variation; Copy number alteration; Endometrial cancer; Glycolytic pathway; Metabolism; Comparative genomic hybridization (aCGH); Genomic instability

[1] Hanahan D., Weinberg R.A.: “Hallmarks of cancer: The next generation”. Cell, 2011, 144, 646.

[2] Graham N.A, Minasyan A., Lomova A., Cass A., Balanis N.G., Friedman M., et al.: “Recurrent patterns of DNA copy number alterations in tumors reflect metabolic selection pressures”. Mol. Syst. Biol., 2017, 13, 914.

[3] Warburg O.: “On the Origin of Cancer Cells”. Science, 1956, 123, 309.

[4] Wu W., Zhao S.: “Metabolic Changes in Cancer: Beyond the Warburg Effect”. Acta Biochim. Biophys. Sin. (Shanghai), 2013, 45, 18.

[5] Stamati K., Mudera V., Cheema U.: “Evolution of oxygen utilization in multicellular organisms and implications for cell signalling in tissue engineering”. J. Tissue Eng., 2011, 2, 2041731411432365.

[6] Bardella C., Pollard P.J., Tomlinson I.: “SDH mutations in cancer”. Biochim. Biophys. Acta, 2011, 1807, 1432.

[7] Rutter J., Winge D.R., Schiffman J.D.: “Succinate dehydrogenase - Assembly, regulation and role in human disease”. Mitochondrion, 2010, 10, 393.

[8] Gaude E., Frezza C.: “Defects in mitochondrial metabolism and cancer”. Cancer Metab., 2014, 2, 10.

[9] Cooper G.M.:“The Mechanism of Oxidative Phosphorylation”. In: The Cell: A Molecular Approach. 2nd ed. Sunderland (MA): Sinauer Associates, 2000.

[10] Alberts B., Johnson A., Lewis J., Raff M., Roberts K.,Walter P.: “ The Mitochondrion”. In: Molecular Biology of the Cell. 4th ed. New York: Garland Science, 2002.

[11] Sullivan L.B., Gui D.Y., Heiden M.G.V.: “Altered metabolite levels in cancer: implications for tumour biology and cancer therapy”. Nat. Rev. Cancer, 2016, 16, 680.

[12] Xiao M., Yang H., Xu W., Ma S., Lin H., Zhu H., et al.: “Inhibition of α-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors”. Genes Dev., 2012, 26, 1326.

[13] Tsuda M., Sugiura T., Ishii T., Ishii N., Aigaki T.: “A mev-1-like dominant-negative SdhC increases oxidative stress and reduces lifespan in Drosophila”. Biochem. Biophys. Res. Commun., 2007, 363, 342.

[14] Hu J., Locasale J.W., Bielas J.H., O’Sullivan J., Sheahan K., Cantley L.C. et al.: “Heterogeneity of tumor-induced gene expression changes in the human metabolic network”. Nat. Biotechnol., 2013, 31, 522.

[15] Israelsen W.J., Heiden M.G.V.: “Pyruvate kinase: function, regulation and role in cancer”. Semin. Cell Dev. Biol., 2015, 43, 43.

[16] Berg J.M., Tymoczko J.L., Lubert S.:“The Glycolytic Pathway Is Tightly Controlled”. In: Biochemistry. 5th ed. New York: W H Freeman, 2002.

[17] Meza N.W., Alonso-Ferrero M.E., Navarro S., Quintana-Bustamante O., Valeri A., Garcia-Gomez M., et al.: “Rescue of Pyruvate Kinase Deficiency in Mice by Gene Therapy Using the Human Isoenzyme”. Mol. Ther., 2009, 17, 2000.

[18] Uhlen M., Zhang C., Lee S., Sjöstedt E., Fagerberg L., Bidkhori G., et al.: “A pathology atlas of the human cancer transcriptome”. Science, 2017, 357. pii: eaan2507.

[19] Thul P.J., Åkesson L., Wiking M., Mahdessian D., Geladaki A., Blal H.A., et al.: “A subcellular map of the human proteome”. Sience, 2017, 356. pii: eaal3321.

[20] Uhlén M., Björling E., Agaton C., Szigyarto C.A., Amini B., Andersen E., et al.: “A Human Protein Atlas for Normal and Cancer Tissues Based on Antibody Proteomics”. Mol. Cell Proteomics, 2005, 4(12),1920.

[21] Chen Y.B., Brannon A.R., Toubaji A., Dudas M.E., Won H.H., AlAhmadie H.A., et al.: “Hereditary leiomyomatosis and renal cell carcinoma syndrome-associated renal cancer: recognition of the syndrome by pathologic features and the utility of detecting aberrant succination by immunohistochemistry”. Am. J. Surg. Pathol., 2014, 38, 627.

[22] King A., Selak M.A., Gottlieb E.: “Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer”. Oncogene, 2006, 25, 4675.

[23] Bardella C., Olivero M., Lorenzato A., Geuna M., Adam J., O’Flaherty L., et al.: “Cells lacking the fumarase tumor suppressor are protected from apoptosis through a HIF-independent, AMPK dependent mechanism”. Mol. Cell Biol., 2012, 32, 3081.

[24] Hu J., Locasale J.W., Bielas J.H., O’Sullivan J., Sheahan K., Cantley L.C., et al.:”Heterogeneity of tumor-induced gene expression changes in the human metabolic network”. Nat. Biotechnol., 2013, 31, 522.

[25] Nguyen A., Loo J.M., Mital R., Weinberg E.M., Man F.Y., Zeng Z., et al.: “PKLR promotes colorectal cancer liver colonization through induction of glutathione synthesis”. J. Clin. Invest., 2016, 126, 681.