[Frontiers In Bioscience, Landmark, 22, 1221-1246, March 1, 2017]

Racial disparity in metabolic regulation of cancer

Kuldeep S. Attri1, Divya Murthy1, Pankaj K. Singh1,2,3,4

1Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, 68198, USA, 2Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska, 68198, USA, 3Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, 68198, USA, 4Department of Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, Omaha, Nebraska, 68198, USA

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Racial disparity in incidence, mortality and risk factors in cancer
4. Metabolic reprogramming in cancer
5. Enzymatic gene mutations as mediators of metabolic rewiring
6. Mutational control of metabolic regulations
6.1. Oncogene-directed metabolic rewiring
6.2. Signaling pathway-mediated metabolic reprogramming
6.2.1. EGFR signaling in cancer
6.2.2. PI3/AKT signaling
6.3. Metabolic reprogramming mediated by the tumor microenvironment
7. Metabolic gene mutations as differential predictors of cancer risk
8. Metabolic profiles as discriminators of cancer risk in different racial groups
9. Racial disparity in genetic regulation of cancer prognosis and therapy
10. Summary and perspective
11. Acknowledgements
12. References

1. ABSTRACT

Genetic mutations and metabolic reprogramming are two key hallmarks of cancer, required for proliferation, invasion, and metastasis of the disease. While genetic mutations, whether inherited or acquired, are critical for the initiation of tumor development, metabolic reprogramming is an effector mechanism imperative for adaptational transition during the progression of cancer. Recent findings in the literature emphasize the significance of molecular cross-talk between these two cellular processes in regulating signaling and differentiation of cancer cells. Genome-wide sequencing analyses of cancer genomes have highlighted the association of various genic mutations in predicting cancer risk and survival. Oncogenic mutational frequency is heterogeneously distributed among various cancer types in different populations, resulting in varying susceptibility to cancer risk. In this review, we explore and discuss the role of genetic mutations in metabolic enzymes and metabolic oncoregulators to stratify cancer risk in persons of different racial backgrounds.

12. REFERENCES

1. N. A. Rosenberg, L. Huang, E. M. Jewett, Z. A. Szpiech, I. Jankovic and M. Boehnke: Genome-wide association studies in diverse populations. Nat Rev Genet, 11(5), 356-66 (2010)
DOI: 10.1038/nrg2760

2. J. C. Lee and M. Parkes: Genome-wide association studies and Crohn’s disease. Brief Funct Genomics, 10(2), 71-6 (2011)
DOI: 10.1093/bfgp/elr009

3. E. Wheeler and I. Barroso: Genome-wide association studies and type 2 diabetes. Brief Funct Genomics, 10(2), 52-60 (2011)
DOI: 10.1093/bfgp/elr008

4. G. I. Evan and K. H. Vousden: Proliferation, cell cycle and apoptosis in cancer. Nature, 411(6835), 342-8 (2001)
DOI: 10.1038/35077213

5. J. K. Wiencke: Impact of race/ethnicity on molecular pathways in human cancer. Nat Rev Cancer, 4(1), 79-84 (2004)
DOI: 10.1038/nrc1257

6. M. Macaluso, M. G. Paggi and A. Giordano: Genetic and epigenetic alterations as hallmarks of the intricate road to cancer. Oncogene, 22(42), 6472-8 (2003)
DOI: 10.1038/sj.onc.1206955

7. K. R. Loeb and L. A. Loeb: Significance of multiple mutations in cancer. Carcinogenesis, 21(3), 379-85 (2000)
DOI: 10.1093/carcin/21.3.379

8. L. M. Dong, J. D. Potter, E. White, C. M. Ulrich, L. R. Cardon and U. Peters: Genetic susceptibility to cancer: the role of polymorphisms in candidate genes. JAMA, 299(20), 2423-36 (2008)
DOI: 10.1001/jama.299.20.2423

9. D. Hanahan and R. A. Weinberg: Hallmarks of cancer: the next generation. Cell, 144(5), 646-74 (2011)
DOI: 10.1016/j.cell.2011.02.013

10. E. Allen, P. Mieville, C. M. Warren, S. Saghafinia, L. Li, M. W. Peng and D. Hanahan: Metabolic Symbiosis Enables Adaptive Resistance to Anti-angiogenic Therapy that Is Dependent on mTOR Signaling. Cell Rep, 15(6), 1144-60 (2016)
DOI: 10.1016/j.celrep.2016.04.029

11. C. A. Stalnecker, S. M. Ulrich, Y. Li, S. Ramachandran, M. K. McBrayer, R. J. DeBerardinis, R. A. Cerione and J. W. Erickson: Mechanism by which a recently discovered allosteric inhibitor blocks glutamine metabolism in transformed cells. Proc Natl Acad Sci U S A, 112(2), 394-9 (2015)
DOI: 10.1073/pnas.1414056112

12. S. Pavlides, D. Whitaker-Menezes, R. Castello-Cros, N. Flomenberg, A. K. Witkiewicz, P. G. Frank, M. C. Casimiro, C. Wang, P. Fortina, S. Addya, R. G. Pestell, U. E. Martinez-Outschoorn, F. Sotgia and M. P. Lisanti: The reverse Warburg effect: aerobic glycolysis in cancer associated fibroblasts and the tumor stroma. Cell Cycle, 8(23), 3984-4001 (2009)
DOI: 10.4161/cc.8.23.10238

13. L. K. Boroughs and R. J. DeBerardinis: Metabolic pathways promoting cancer cell survival and growth. Nat Cell Biol, 17(4), 351-9 (2015)
DOI: 10.1038/ncb3124

14. A. A. Alizadeh, V. Aranda, A. Bardelli, C. Blanpain, C. Bock, C. Borowski, C. Caldas, A. Califano, M. Doherty, M. Elsner, M. Esteller, R. Fitzgerald, J. O. Korbel, P. Lichter, C. E. Mason, N. Navin, D. Pe’er, K. Polyak, C. W. Roberts, L. Siu, A. Snyder, H. Stower, C. Swanton, R. G. Verhaak, J. C. Zenklusen, J. Zuber and J. Zucman-Rossi: Toward understanding and exploiting tumor heterogeneity. Nat Med, 21(8), 846-53 (2015)
DOI: 10.1038/nm.3915

15. N. A. Howlader N, Krapcho M, Miller D, Bishop K, Altekruse SF, Kosary CL, Yu M, Ruhl J, Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). SEER Cancer Statistics Review, 1975-2013, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2013/, based on November 2015 SEER data submission, posted to the SEER web site, April 2016.: In,

16. A. M. McCarthy, J. Yang and K. Armstrong: Increasing disparities in breast cancer mortality from 1979 to 2010 for US black women aged 20 to 49 years. Am J Public Health, 105 Suppl 3, S446-8 (2015)
DOI: 10.2105/AJPH.2014.302297

17. P. Maisonneuve and A. B. Lowenfels: Risk factors for pancreatic cancer: a summary review of meta-analytical studies. Int J Epidemiol, 44(1), 186-98 (2015)
DOI: 10.1093/ije/dyu240

18. C. M. Johnson, C. Wei, J. E. Ensor, D. J. Smolenski, C. I. Amos, B. Levin and D. A. Berry: Meta-analyses of colorectal cancer risk factors. Cancer Causes Control, 24(6), 1207-22 (2013)
DOI: 10.1007/s10552-013-0201-5

19. Z. Gong, C. B. Ambrosone, S. E. McCann, G. Zirpoli, U. Chandran, C. C. Hong, D. H. Bovbjerg, L. Jandorf, G. Ciupak, K. Pawlish, Q. Lu, H. Hwang, T. Khoury, B. Wiam and E. V. Bandera: Associations of dietary folate, Vitamins B6 and B12 and methionine intake with risk of breast cancer among African American and European American women. Int J Cancer, 134(6), 1422-35 (2014)
DOI: 10.1002/ijc.28466

20. I. T. Gram, S. Y. Park, L. N. Kolonel, G. Maskarinec, L. R. Wilkens, B. E. Henderson and L. Le Marchand: Smoking and Risk of Breast Cancer in a Racially/Ethnically Diverse Population of Mainly Women Who Do Not Drink Alcohol: The MEC Study. Am J Epidemiol, 182(11), 917-25 (2015)
DOI: 10.1093/aje/kwv092

21. C. E. DeSantis, R. L. Siegel, A. G. Sauer, K. D. Miller, S. A. Fedewa, K. I. Alcaraz and A. Jemal: Cancer statistics for African Americans, 2016: Progress and opportunities in reducing racial disparities. CA Cancer J Clin, 66(4), 290-308 (2016)
DOI: 10.3322/caac.21340

22. J. N. Curran, E. Garrett-Mayer, M. J. Carpenter, M. E. Ford, G. A. Silvestri, D. T. Lackland and A. J. Alberg: Cigarette smoking and the risk of dying from tobacco-related malignancies by race. Anticancer Res, 31(11), 3891-5 (2011)

23. C. A. Haiman, D. O. Stram, L. R. Wilkens, M. C. Pike, L. N. Kolonel, B. E. Henderson and L. Le Marchand: Ethnic and racial differences in the smoking-related risk of lung cancer. N Engl J Med, 354(4), 333-42 (2006)
DOI: 10.1056/NEJMoa033250

24. Y. M. Kanaan, B. P. Sampey, D. Beyene, A. K. Esnakula, T. J. Naab, L. J. Ricks-Santi, S. Dasi, A. Day, K. W. Blackman, W. Frederick, R. L. Copeland, Sr., E. Gabrielson and R. L. Dewitty, Jr.: Metabolic profile of triple-negative breast cancer in African-American women reveals potential biomarkers of aggressive disease. Cancer Genomics Proteomics, 11(6), 279-94 (2014)

25. C. J. Tsai and E. L. Giovannucci: Hyperinsulinemia, insulin resistance, vitamin D, and colorectal cancer among whites and African Americans. Dig Dis Sci, 57(10), 2497-503 (2012)
DOI: 10.1007/s10620-012-2198-0

26. E. S. Ong, L. Zou, S. Li, P. Y. Cheah, K. W. Eu and C. N. Ong: Metabolic profiling in colorectal cancer reveals signature metabolic shifts during tumorigenesis. Mol Cell Proteomics (2010)
DOI: 10.1074/mcp.M900551-MCP200

27. P. P. Cavicchia, S. A. Adams, S. E. Steck, J. R. Hussey, J. Liu, V. G. Daguise and J. R. Hebert: Racial disparities in colorectal cancer incidence by type 2 diabetes mellitus status. Cancer Causes Control, 24(2), 277-85 (2013)
DOI: 10.1007/s10552-012-0095-7

28. C. C. Murphy, C. F. Martin and R. S. Sandler: Racial differences in obesity measures and risk of colorectal adenomas in a large screening population. Nutr Cancer, 67(1), 98-104 (2015)
DOI: 10.1080/01635581.2015.976316

29. N. Bardeesy and R. A. DePinho: Pancreatic cancer biology and genetics. Nat Rev Cancer, 2(12), 897-909 (2002)
DOI: 10.1038/nrc949

30. L. D. Arnold, A. V. Patel, Y. Yan, E. J. Jacobs, M. J. Thun, E. E. Calle and G. A. Colditz: Are racial disparities in pancreatic cancer explained by smoking and overweight/obesity? Cancer Epidemiol Biomarkers Prev, 18(9), 2397-405 (2009)
DOI: 10.1158/1055-9965.EPI-09-0080

31. D. T. Silverman, R. N. Hoover, L. M. Brown, G. M. Swanson, M. Schiffman, R. S. Greenberg, R. B. Hayes, K. D. Lillemoe, J. B. Schoenberg, A. G. Schwartz, J. Liff, L. M. Pottern and J. F. Fraumeni, Jr.: Why do Black Americans have a higher risk of pancreatic cancer than White Americans? Epidemiology, 14(1), 45-54 (2003)
DOI: 10.1097/00001648-200301000-00013

32. D. Li, H. Tang, M. M. Hassan, E. A. Holly, P. M. Bracci and D. T. Silverman: Diabetes and risk of pancreatic cancer: a pooled analysis of three large case-control studies. Cancer Causes Control, 22(2), 189-97 (2011)
DOI: 10.1007/s10552-010-9686-3

33. R. A. Cairns, I. S. Harris and T. W. Mak: Regulation of cancer cell metabolism. Nat Rev Cancer, 11(2), 85-95 (2011)
DOI: 10.1038/nrc2981

34. M. G. Vander Heiden, L. C. Cantley and C. B. Thompson: Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science, 324(5930), 1029-33 (2009)
DOI: 10.1126/science.1160809

35. K. Adekola, S. T. Rosen and M. Shanmugam: Glucose transporters in cancer metabolism. Curr Opin Oncol, 24(6), 650-4 (2012)
DOI: 10.1097/CCO.0b013e328356da72

36. S. Y. Lunt and M. G. Vander Heiden: Aerobic glycolysis: meeting the metabolic requirements of cell proliferation. Annu Rev Cell Dev Biol, 27, 441-64 (2011)
DOI: 10.1146/annurev-cellbio-092910-154237

37. M. G. Vander Heiden, S. Y. Lunt, T. L. Dayton, B. P. Fiske, W. J. Israelsen, K. R. Mattaini, N. I. Vokes, G. Stephanopoulos, L. C. Cantley, C. M. Metallo and J. W. Locasale: Metabolic pathway alterations that support cell proliferation. Cold Spring Harb Symp Quant Biol, 76, 325-34 (2011)
DOI: 10.1101/sqb.2012.76.010900

38. P. E. Porporato, S. Dhup, R. K. Dadhich, T. Copetti and P. Sonveaux: Anticancer targets in the glycolytic metabolism of tumors: a comprehensive review. Front Pharmacol, 2, 49 (2011)
DOI: 10.3389/fphar.2011.00049

39. K. C. Patra and N. Hay: The pentose phosphate pathway and cancer. Trends Biochem Sci, 39(8), 347-54 (2014)
DOI: 10.1016/j.tibs.2014.06.005

40. T. Atsumi, J. Chesney, C. Metz, L. Leng, S. Donnelly, Z. Makita, R. Mitchell and R. Bucala: High expression of inducible 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (iPFK-2; PFKFB3) in human cancers. Cancer Res, 62(20), 5881-7 (2002)

41. V. R. Fantin, J. St-Pierre and P. Leder: Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance. Cancer Cell, 9(6), 425-34 (2006)
DOI: 10.1016/j.ccr.2006.04.023

42. H. R. Christofk, M. G. Vander Heiden, M. H. Harris, A. Ramanathan, R. E. Gerszten, R. Wei, M. D. Fleming, S. L. Schreiber and L. C. Cantley: The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature, 452(7184), 230-3 (2008)
DOI: 10.1038/nature06734

43. A. Vazquez, J. Liu, Y. Zhou and Z. N. Oltvai: Catabolic efficiency of aerobic glycolysis: the Warburg effect revisited. BMC Syst Biol, 4, 58 (2010)
DOI: 10.1186/1752-0509-4-58

44. L. R. Gray, S. C. Tompkins and E. B. Taylor: Regulation of pyruvate metabolism and human disease. Cell Mol Life Sci, 71(14), 2577-604 (2014)
DOI: 10.1007/s00018-013-1539-2

45. R. Lin, R. Tao, X. Gao, T. Li, X. Zhou, K. L. Guan, Y. Xiong and Q. Y. Lei: Acetylation stabilizes ATP-citrate lyase to promote lipid biosynthesis and tumor growth. Mol Cell, 51(4), 506-18 (2013)
DOI: 10.1016/j.molcel.2013.07.002

46. C. Munoz-Pinedo, N. El Mjiyad and J. E. Ricci: Cancer metabolism: current perspectives and future directions. Cell Death Dis, 3, e248 (2012)
DOI: 10.1038/cddis.2011.123

47. M. van Geldermalsen, Q. Wang, R. Nagarajah, A. D. Marshall, A. Thoeng, D. Gao, W. Ritchie, Y. Feng, C. G. Bailey, N. Deng, K. Harvey, J. M. Beith, C. I. Selinger, S. A. O’Toole, J. E. Rasko and J. Holst: ASCT2/SLC1A5 controls glutamine uptake and tumour growth in triple-negative basal-like breast cancer. Oncogene, 35(24), 3201-8 (2016)
DOI: 10.1038/onc.2015.381

48. C. V. Dang: Rethinking the Warburg effect with Myc micromanaging glutamine metabolism. Cancer Res, 70(3), 859-62 (2010)
DOI: 10.1158/0008-5472.CAN-09-3556

49. D. Wen, D. Liu, J. Tang, L. Dong, Y. Liu, Z. Tao, J. Wan, D. Gao, L. Wang, H. Sun, J. Fan and W. Wu: Malic enzyme 1 induces epithelial-mesenchymal transition and indicates poor prognosis in hepatocellular carcinoma. Tumour Biol, 36(8), 6211-21 (2015)
DOI: 10.1007/s13277-015-3306-5

50. R. J. Deberardinis, N. Sayed, D. Ditsworth and C. B. Thompson: Brick by brick: metabolism and tumor cell growth. Curr Opin Genet Dev, 18(1), 54-61 (2008)
DOI: 10.1016/j.gde.2008.02.003

51. C. M. Metallo, P. A. Gameiro, E. L. Bell, K. R. Mattaini, J. Yang, K. Hiller, C. M. Jewell, Z. R. Johnson, D. J. Irvine, L. Guarente, J. K. Kelleher, M. G. Vander Heiden, O. Iliopoulos and G. Stephanopoulos: Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature, 481(7381), 380-4 (2012)

52. A. R. Mullen, W. W. Wheaton, E. S. Jin, P. H. Chen, L. B. Sullivan, T. Cheng, Y. Yang, W. M. Linehan, N. S. Chandel and R. J. DeBerardinis: Reductive carboxylation supports growth in tumour cells with defective mitochondria. Nature, 481(7381), 385-8 (2012)

53. J. Son, C. A. Lyssiotis, H. Ying, X. Wang, S. Hua, M. Ligorio, R. M. Perera, C. R. Ferrone, E. Mullarky, N. Shyh-Chang, Y. Kang, J. B. Fleming, N. Bardeesy, J. M. Asara, M. C. Haigis, R. A. DePinho, L. C. Cantley and A. C. Kimmelman: Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature, 496(7443), 101-5 (2013)
DOI: 10.1038/nature12040

54. R. J. DeBerardinis, A. Mancuso, E. Daikhin, I. Nissim, M. Yudkoff, S. Wehrli and C. B. Thompson: Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc Natl Acad Sci U S A, 104(49), 19345-50 (2007)
DOI: 10.1073/pnas.0709747104

55. C. Yang, B. Ko, C. T. Hensley, L. Jiang, A. T. Wasti, J. Kim, J. Sudderth, M. A. Calvaruso, L. Lumata, M. Mitsche, J. Rutter, M. E. Merritt and R. J. DeBerardinis: Glutamine oxidation maintains the TCA cycle and cell survival during impaired mitochondrial pyruvate transport. Mol Cell, 56(3), 414-24 (2014)
DOI: 10.1016/j.molcel.2014.09.025

56. A. E. Vaughn and M. Deshmukh: Glucose metabolism inhibits apoptosis in neurons and cancer cells by redox inactivation of cytochrome c. Nat Cell Biol, 10(12), 1477-83 (2008)
DOI: 10.1038/ncb1807

57. X. Dong, H. Tang, K. R. Hess, J. L. Abbruzzese and D. Li: Glucose metabolism gene polymorphisms and clinical outcome in pancreatic cancer. Cancer, 117(3), 480-91 (2011)
DOI: 10.1002/cncr.25612

58. S. J. Kim, S. H. Hwang, I. J. Kim, M. K. Lee, C. H. Lee, S. Y. Lee and E. Y. Lee: The association of 18F-deoxyglucose (FDG) uptake of PET with polymorphisms in the glucose transporter gene (SLC2A1) and hypoxia-related genes (HIF1A, VEGFA, APEX1) in non-small cell lung cancer. SLC2A1 polymorphisms and FDG-PET in NSCLC patients. J Exp Clin Cancer Res, 29, 69 (2010)
DOI: 10.1186/1756-9966-29-69

59. B. E. Baysal, R. E. Ferrell, J. E. Willett-Brozick, E. C. Lawrence, D. Myssiorek, A. Bosch, A. van der Mey, P. E. Taschner, W. S. Rubinstein, E. N. Myers, C. W. Richard, 3rd, C. J. Cornelisse, P. Devilee and B. Devlin: Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science, 287(5454), 848-51 (2000)
DOI: 10.1126/science.287.5454.848

60. I. P. Tomlinson, N. A. Alam, A. J. Rowan, E. Barclay, E. E. Jaeger, D. Kelsell, I. Leigh, P. Gorman, H. Lamlum, S. Rahman, R. R. Roylance, S. Olpin, S. Bevan, K. Barker, N. Hearle, R. S. Houlston, M. Kiuru, R. Lehtonen, A. Karhu, S. Vilkki, P. Laiho, C. Eklund, O. Vierimaa, K. Aittomaki, M. Hietala, P. Sistonen, A. Paetau, R. Salovaara, R. Herva, V. Launonen, L. A. Aaltonen and C. Multiple Leiomyoma: Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Genet, 30(4), 406-10 (2002)
DOI: 10.1038/ng849

61. H. Yan, D. W. Parsons, G. Jin, R. McLendon, B. A. Rasheed, W. Yuan, I. Kos, I. Batinic-Haberle, S. Jones, G. J. Riggins, H. Friedman, A. Friedman, D. Reardon, J. Herndon, K. W. Kinzler, V. E. Velculescu, B. Vogelstein and D. D. Bigner: IDH1 and IDH2 mutations in gliomas. N Engl J Med, 360(8), 765-73 (2009)
DOI: 10.1056/NEJMoa0808710

62. X. Guo, D. Li, Y. Wu, Y. Chen, X. Zhou, X. Wang, X. Huang, X. Li, H. Yang and J. Xing: Genetic variants in genes of tricarboxylic acid cycle key enzymes are associated with prognosis of patients with non-small cell lung cancer. Lung Cancer, 87(2), 162-8 (2015)
DOI: 10.1016/j.lungcan.2014.12.005

63. P. J. Pollard, J. J. Briere, N. A. Alam, J. Barwell, E. Barclay, N. C. Wortham, T. Hunt, M. Mitchell, S. Olpin, S. J. Moat, I. P. Hargreaves, S. J. Heales, Y. L. Chung, J. R. Griffiths, A. Dalgleish, J. A. McGrath, M. J. Gleeson, S. V. Hodgson, R. Poulsom, P. Rustin and I. P. Tomlinson: Accumulation of Krebs cycle intermediates and over-expression of HIF1alpha in tumours which result from germline FH and SDH mutations. Hum Mol Genet, 14(15), 2231-9 (2005)
DOI: 10.1093/hmg/ddi227

64. M. A. Selak, S. M. Armour, E. D. MacKenzie, H. Boulahbel, D. G. Watson, K. D. Mansfield, Y. Pan, M. C. Simon, C. B. Thompson and E. Gottlieb: Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Cancer Cell, 7(1), 77-85 (2005)
DOI: 10.1016/j.ccr.2004.11.022

65. J. S. Isaacs, Y. J. Jung, D. R. Mole, S. Lee, C. Torres-Cabala, Y. L. Chung, M. Merino, J. Trepel, B. Zbar, J. Toro, P. J. Ratcliffe, W. M. Linehan and L. Neckers: HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability. Cancer Cell, 8(2), 143-53 (2005)
DOI: 10.1016/j.ccr.2005.06.017

66. S. Zhao, Y. Lin, W. Xu, W. Jiang, Z. Zha, P. Wang, W. Yu, Z. Li, L. Gong, Y. Peng, J. Ding, Q. Lei, K. L. Guan and Y. Xiong: Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1alpha. Science, 324(5924), 261-5 (2009)
DOI: 10.1126/science.1170944

67. X. Guo, C. Chen, B. Liu, Y. Wu, Y. Chen, X. Zhou, X. Huang, X. Li, H. Yang, Z. Chen and J. Xing: Genetic variations in monocarboxylate transporter genes as predictors of clinical outcomes in non-small cell lung cancer. Tumour Biol, 36(5), 3931-9 (2015)
DOI: 10.1007/s13277-014-3036-0

68. F. Fei, X. Guo, Y. Chen, X. Liu, J. Tu, J. Xing, Z. Chen, J. Ji and X. He: Polymorphisms of monocarboxylate transporter genes are associated with clinical outcomes in patients with colorectal cancer. J Cancer Res Clin Oncol, 141(6), 1095-102 (2015)
DOI: 10.1007/s00432-014-1877-y

69. S. Xie, F. Zhou, J. Wang, H. Cao, Y. Chen, X. Liu, Z. Zhang, J. Dai and X. He: Functional polymorphisms of ATP citrate lyase gene predicts clinical outcome of patients with advanced colorectal cancer. World J Surg Oncol, 13, 42 (2015)
DOI: 10.1186/s12957-015-0440-x

70. J. G. Paez, P. A. Janne, J. C. Lee, S. Tracy, H. Greulich, S. Gabriel, P. Herman, F. J. Kaye, N. Lindeman, T. J. Boggon, K. Naoki, H. Sasaki, Y. Fujii, M. J. Eck, W. R. Sellers, B. E. Johnson and M. Meyerson: EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science, 304(5676), 1497-500 (2004)
DOI: 10.1126/science.1099314

71. S. Y. Hong, F. X. Yu, Y. Luo and T. Hagen: Oncogenic activation of the PI3K/Akt pathway promotes cellular glucose uptake by downregulating the expression of thioredoxin-interacting protein. Cell Signal, 28(5), 377-83 (2016)
DOI: 10.1016/j.cellsig.2016.01.011

72. C. M. Ardito, B. M. Gruner, K. K. Takeuchi, C. Lubeseder-Martellato, N. Teichmann, P. K. Mazur, K. E. Delgiorno, E. S. Carpenter, C. J. Halbrook, J. C. Hall, D. Pal, T. Briel, A. Herner, M. Trajkovic-Arsic, B. Sipos, G. Y. Liou, P. Storz, N. R. Murray, D. W. Threadgill, M. Sibilia, M. K. Washington, C. L. Wilson, R. M. Schmid, E. W. Raines, H. C. Crawford and J. T. Siveke: EGF receptor is required for KRAS-induced pancreatic tumorigenesis. Cancer Cell, 22(3), 304-17 (2012)
DOI: 10.1016/j.ccr.2012.07.024

73. R. B. Corcoran, H. Ebi, A. B. Turke, E. M. Coffee, M. Nishino, A. P. Cogdill, R. D. Brown, P. Della Pelle, D. Dias-Santagata, K. E. Hung, K. T. Flaherty, A. Piris, J. A. Wargo, J. Settleman, M. Mino-Kenudson and J. A. Engelman: EGFR-mediated re-activation of MAPK signaling contributes to insensitivity of BRAF mutant colorectal cancers to RAF inhibition with vemurafenib. Cancer Discov, 2(3), 227-35 (2012)
DOI: 10.1158/2159-8290.CD-11-0341

74. M. Iwamoto, K. Kawada, Y. Nakamoto, Y. Itatani, S. Inamoto, K. Toda, H. Kimura, T. Sasazuki, S. Shirasawa, H. Okuyama, M. Inoue, S. Hasegawa, K. Togashi and Y. Sakai: Regulation of 18F-FDG accumulation in colorectal cancer cells with mutated KRAS. J Nucl Med, 55(12), 2038-44 (2014)
DOI: 10.2967/jnumed.114.142927

75. I. A. Prior, P. D. Lewis and C. Mattos: A comprehensive survey of Ras mutations in cancer. Cancer Res, 72(10), 2457-67 (2012)
DOI: 10.1158/0008-5472.CAN-11-2612

76. E. M. Kerr, E. Gaude, F. K. Turrell, C. Frezza and C. P. Martins: Mutant Kras copy number defines metabolic reprogramming and therapeutic susceptibilities. Nature, 531(7592), 110-3 (2016)
DOI: 10.1038/nature16967

77. H. Davies, G. R. Bignell, C. Cox, P. Stephens, S. Edkins, S. Clegg, J. Teague, H. Woffendin, M. J. Garnett, W. Bottomley, N. Davis, E. Dicks, R. Ewing, Y. Floyd, K. Gray, S. Hall, R. Hawes, J. Hughes, V. Kosmidou, A. Menzies, C. Mould, A. Parker, C. Stevens, S. Watt, S. Hooper, R. Wilson, H. Jayatilake, B. A. Gusterson, C. Cooper, J. Shipley, D. Hargrave, K. Pritchard-Jones, N. Maitland, G. Chenevix-Trench, G. J. Riggins, D. D. Bigner, G. Palmieri, A. Cossu, A. Flanagan, A. Nicholson, J. W. Ho, S. Y. Leung, S. T. Yuen, B. L. Weber, H. F. Seigler, T. L. Darrow, H. Paterson, R. Marais, C. J. Marshall, R. Wooster, M. R. Stratton and P. A. Futreal: Mutations of the BRAF gene in human cancer. Nature, 417(6892), 949-54 (2002)
DOI: 10.1038/nature00766

78. R. Haq, J. Shoag, P. Andreu-Perez, S. Yokoyama, H. Edelman, G. C. Rowe, D. T. Frederick, A. D. Hurley, A. Nellore, A. L. Kung, J. A. Wargo, J. S. Song, D. E. Fisher, Z. Arany and H. R. Widlund: Oncogenic BRAF regulates oxidative metabolism via PGC1alpha and MITF. Cancer Cell, 23(3), 302-15 (2013)
DOI: 10.1016/j.ccr.2013.02.003

79. D. P. Vivekananthan, V. B. Patel and D. J. Moliterno: Glycoprotein IIb/IIIa antagonism and fibrinolytic therapy for acute myocardial infarction. J Interv Cardiol, 15(2), 131-9 (2002)
DOI: 10.1111/j.1540-8183.2002.tb01045.x

80. S. J. Yeung, J. Pan and M. H. Lee: Roles of p53, MYC and HIF-1 in regulating glycolysis - the seventh hallmark of cancer. Cell Mol Life Sci, 65(24), 3981-99 (2008)
DOI: 10.1007/s00018-008-8224-x

81. N. Bardeesy, A. J. Aguirre, G. C. Chu, K. H. Cheng, L. V. Lopez, A. F. Hezel, B. Feng, C. Brennan, R. Weissleder, U. Mahmood, D. Hanahan, M. S. Redston, L. Chin and R. A. Depinho: Both p16(Ink4a) and the p19(Arf)-p53 pathway constrain progression of pancreatic adenocarcinoma in the mouse. Proc Natl Acad Sci U S A, 103(15), 5947-52 (2006)
DOI: 10.1073/pnas.0601273103

82. P. K. Singh, K. Mehla, M. A. Hollingsworth and K. R. Johnson: Regulation of Aerobic Glycolysis by microRNAs in Cancer. Mol Cell Pharmacol, 3(3), 125-134 (2011)

83. J. Boada, T. Roig, X. Perez, A. Gamez, R. Bartrons, M. Cascante and J. Bermudez: Cells overexpressing fructose-2,6-bisphosphatase showed enhanced pentose phosphate pathway flux and resistance to oxidative stress. FEBS Lett, 480(2-3), 261-4 (2000)
DOI: 10.1016/S0014-5793(00)01950-5

84. A. Langerod, H. Zhao, O. Borgan, J. M. Nesland, I. R. Bukholm, T. Ikdahl, R. Karesen, A. L. Borresen-Dale and S. S. Jeffrey: TP53 mutation status and gene expression profiles are powerful prognostic markers of breast cancer. Breast Cancer Res, 9(3), R30 (2007)
DOI: 10.1186/bcr1675

85. Y. Wang, A. Helland, R. Holm, H. Skomedal, V. M. Abeler, H. E. Danielsen, C. G. Trope, A. L. Borresen-Dale and G. B. Kristensen: TP53 mutations in early-stage ovarian carcinoma, relation to long-term survival. Br J Cancer, 90(3), 678-85 (2004)
DOI: 10.1038/sj.bjc.6601537

86. M. Olivier, M. Hollstein and P. Hainaut: TP53 mutations in human cancers: origins, consequences, and clinical use. Cold Spring Harb Perspect Biol, 2(1), a001008 (2010)
DOI: 10.1101/cshperspect.a001008

87. M. J. Scian, K. E. Stagliano, M. A. Ellis, S. Hassan, M. Bowman, M. F. Miles, S. P. Deb and S. Deb: Modulation of gene expression by tumor-derived p53 mutants. Cancer Res, 64(20), 7447-54 (2004)
DOI: 10.1158/0008-5472.CAN-04-1568

88. H. Zheng, H. Ying, H. Yan, A. C. Kimmelman, D. J. Hiller, A. J. Chen, S. R. Perry, G. Tonon, G. C. Chu, Z. Ding, J. M. Stommel, K. L. Dunn, R. Wiedemeyer, M. J. You, C. Brennan, Y. A. Wang, K. L. Ligon, W. H. Wong, L. Chin and R. A. dePinho: Pten and p53 converge on c-Myc to control differentiation, self-renewal, and transformation of normal and neoplastic stem cells in glioblastoma. Cold Spring Harb Symp Quant Biol, 73, 427-37 (2008)
DOI: 10.1101/sqb.2008.73.047

89. H. Shim, C. Dolde, B. C. Lewis, C. S. Wu, G. Dang, R. A. Jungmann, R. Dalla-Favera and C. V. Dang: c-Myc transactivation of LDH-A: implications for tumor metabolism and growth. Proc Natl Acad Sci U S A, 94(13), 6658-63 (1997)
DOI: 10.1073/pnas.94.13.6658

90. C. V. Dang, A. Le and P. Gao: MYC-induced cancer cell energy metabolism and therapeutic opportunities. Clin Cancer Res, 15(21), 6479-83 (2009)
DOI: 10.1158/1078-0432.CCR-09-0889

91. J. W. Kim, P. Gao, Y. C. Liu, G. L. Semenza and C. V. Dang: Hypoxia-inducible factor 1 and dysregulated c-Myc cooperatively induce vascular endothelial growth factor and metabolic switches hexokinase 2 and pyruvate dehydrogenase kinase 1. Mol Cell Biol, 27(21), 7381-93 (2007)
DOI: 10.1128/MCB.00440-07

92. D. R. Wise, R. J. DeBerardinis, A. Mancuso, N. Sayed, X. Y. Zhang, H. K. Pfeiffer, I. Nissim, E. Daikhin, M. Yudkoff, S. B. McMahon and C. B. Thompson: Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proc Natl Acad Sci U S A, 105(48), 18782-7 (2008)
DOI: 10.1073/pnas.0810199105

93. T. Jacks and R. A. Weinberg: The expanding role of cell cycle regulators. Science, 280(5366), 1035-6 (1998)
DOI: 10.1126/science.280.5366.1035

94. M. Privat, N. Radosevic-Robin, C. Aubel, A. Cayre, F. Penault-Llorca, G. Marceau, V. Sapin, Y. J. Bignon and D. Morvan: BRCA1 induces major energetic metabolism reprogramming in breast cancer cells. PLoS One, 9(7), e102438 (2014)
DOI: 10.1371/journal.pone.0102438

95. J. Brunet, A. Vazquez-Martin, R. Colomer, B. Grana-Suarez, B. Martin-Castillo and J. A. Menendez: BRCA1 and acetyl-CoA carboxylase: the metabolic syndrome of breast cancer. Mol Carcinog, 47(2), 157-63 (2008)
DOI: 10.1002/mc.20364

96. D. Li, F. F. Bi, N. N. Chen, J. M. Cao, W. P. Sun, Y. M. Zhou, C. Y. Li and Q. Yang: A novel crosstalk between BRCA1 and sirtuin 1 in ovarian cancer. Sci Rep, 4, 6666 (2014)
DOI: 10.1038/srep06666

97. S. Pruthi, B. S. Gostout and N. M. Lindor: Identification and Management of Women With BRCA Mutations or Hereditary Predisposition for Breast and Ovarian Cancer. Mayo Clin Proc, 85(12), 1111-20 (2010)
DOI: 10.4065/mcp.2010.0414

98. T. Xiang, A. Ohashi, Y. Huang, T. K. Pandita, T. Ludwig, S. N. Powell and Q. Yang: Negative Regulation of AKT Activation by BRCA1. Cancer Res, 68(24), 10040-4 (2008)
DOI: 10.1158/0008-5472.CAN-08-3009

99. H. J. Kang, H. J. Kim, J. K. Rih, T. L. Mattson, K. W. Kim, C. H. Cho, J. S. Isaacs and I. Bae: BRCA1 plays a role in the hypoxic response by regulating HIF-1alpha stability and by modulating vascular endothelial growth factor expression. J Biol Chem, 281(19), 13047-56 (2006)
DOI: 10.1074/jbc.M513033200

100. M. J. Martinez-Calatrava, J. L. Gonzalez-Sanchez, M. T. Martinez-Larrad, M. Perez-Barba and M. Serrano-Rios: Common haplotypes of the C-reactive protein gene and circulating leptin levels influence the interindividual variability in serum C-reactive protein levels. The Segovia study. Thromb Haemost, 98(5), 1088-95 (2007)
DOI: 10.1160/th07-03-0231

101. K. Moreau, E. Dizin, H. Ray, C. Luquain, E. Lefai, F. Foufelle, M. Billaud, G. M. Lenoir and N. D. Venezia: BRCA1 affects lipid synthesis through its interaction with acetyl-CoA carboxylase. J Biol Chem, 281(6), 3172-81 (2006)
DOI: 10.1074/jbc.M504652200

102. S. O. Lim, C. W. Li, W. Xia, H. H. Lee, S. S. Chang, J. Shen, J. L. Hsu, D. Raftery, D. Djukovic, H. Gu, W. C. Chang, H. L. Wang, M. L. Chen, L. Huo, C. H. Chen, Y. Wu, A. Sahin, S. M. Hanash, G. N. Hortobagyi and M. C. Hung: EGFR Signaling Enhances Aerobic Glycolysis in Triple-Negative Breast Cancer Cells to Promote Tumor Growth and Immune Escape. Cancer Res, 76(5), 1284-96 (2016)
DOI: 10.1158/0008-5472.CAN-15-2478

103. A. F. Gazdar: Activating and resistance mutations of EGFR in non-small-cell lung cancer: role in clinical response to EGFR tyrosine kinase inhibitors. Oncogene, 28 Suppl 1, S24-31 (2009)
DOI: 10.1038/onc.2009.198

104. D. Romano, H. Maccario, C. Doherty, N. P. Quinn, W. Kolch and D. Matallanas: The differential effects of wild-type and mutated K-Ras on MST2 signaling are determined by K-Ras activation kinetics. Mol Cell Biol, 33(9), 1859-68 (2013)
DOI: 10.1128/MCB.01414-12

105. E. Castellano and J. Downward: Role of RAS in the regulation of PI 3-kinase. Curr Top Microbiol Immunol, 346, 143-69 (2010)
DOI: 10.1007/82_2010_56

106. T. Regad: Targeting RTK Signaling Pathways in Cancer. Cancers (Basel), 7(3), 1758-84 (2015)
DOI: 10.3390/cancers7030860

107. P. Liu, H. Cheng, T. M. Roberts and J. J. Zhao: Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov, 8(8), 627-44 (2009)
DOI: 10.1038/nrd2926

108. A. Barthel, S. T. Okino, J. Liao, K. Nakatani, J. Li, J. P. Whitlock, Jr. and R. A. Roth: Regulation of GLUT1 gene transcription by the serine/threonine kinase Akt1. J Biol Chem, 274(29), 20281-6 (1999)
DOI: 10.1074/jbc.274.29.20281

109. J. Deprez, D. Vertommen, D. R. Alessi, L. Hue and M. H. Rider: Phosphorylation and activation of heart 6-phosphofructo-2-kinase by protein kinase B and other protein kinases of the insulin signaling cascades. J Biol Chem, 272(28), 17269-75 (1997)
DOI: 10.1074/jbc.272.28.17269

110. K. Gottlob, N. Majewski, S. Kennedy, E. Kandel, R. B. Robey and N. Hay: Inhibition of early apoptotic events by Akt/PKB is dependent on the first committed step of glycolysis and mitochondrial hexokinase. Genes Dev, 15(11), 1406-18 (2001)
DOI: 10.1101/gad.889901

111. D. C. Berwick, I. Hers, K. J. Heesom, S. K. Moule and J. M. Tavare: The identification of ATP-citrate lyase as a protein kinase B (Akt) substrate in primary adipocytes. J Biol Chem, 277(37), 33895-900 (2002)
DOI: 10.1074/jbc.M204681200

112. Y. A. Yang, W. F. Han, P. J. Morin, F. J. Chrest and E. S. Pizer: Activation of fatty acid synthesis during neoplastic transformation: role of mitogen-activated protein kinase and phosphatidylinositol 3-kinase. Exp Cell Res, 279(1), 80-90 (2002)
DOI: 10.1006/excr.2002.5600

113. E. B. Rankin and A. J. Giaccia: The role of hypoxia-inducible factors in tumorigenesis. Cell Death Differ, 15(4), 678-85 (2008)
DOI: 10.1038/cdd.2008.21

114. F. Hirschhaeuser, U. G. Sattler and W. Mueller-Klieser: Lactate: a metabolic key player in cancer. Cancer Res, 71(22), 6921-5 (2011)
DOI: 10.1158/0008-5472.CAN-11-1457

115. G. L. Semenza: HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations. J Clin Invest, 123(9), 3664-71 (2013)
DOI: 10.1172/JCI67230

116. C. J. Hu, L. Y. Wang, L. A. Chodosh, B. Keith and M. C. Simon: Differential roles of hypoxia-inducible factor 1alpha (HIF-1alpha) and HIF-2alpha in hypoxic gene regulation. Mol Cell Biol, 23(24), 9361-74 (2003)
DOI: 10.1128/MCB.23.24.9361-9374.2003

117. M. Hayashi, M. Sakata, T. Takeda, T. Yamamoto, Y. Okamoto, K. Sawada, A. Kimura, R. Minekawa, M. Tahara, K. Tasaka and Y. Murata: Induction of glucose transporter 1 expression through hypoxia-inducible factor 1alpha under hypoxic conditions in trophoblast-derived cells. J Endocrinol, 183(1), 145-54 (2004)
DOI: 10.1677/joe.1.05599

118. Y. Liu, Y. M. Li, R. F. Tian, W. P. Liu, Z. Fei, Q. F. Long, X. A. Wang and X. Zhang: The expression and significance of HIF-1alpha and GLUT-3 in glioma. Brain Res, 1304, 149-54 (2009)
DOI: 10.1016/j.brainres.2009.09.083

119. M. Obach, A. Navarro-Sabate, J. Caro, X. Kong, J. Duran, M. Gomez, J. C. Perales, F. Ventura, J. L. Rosa and R. Bartrons: 6-Phosphofructo-2-kinase (pfkfb3) gene promoter contains hypoxia-inducible factor-1 binding sites necessary for transactivation in response to hypoxia. J Biol Chem, 279(51), 53562-70 (2004)
DOI: 10.1074/jbc.M406096200

120. S. Kress, A. Stein, P. Maurer, B. Weber, J. Reichert, A. Buchmann, P. Huppert and M. Schwarz: Expression of hypoxia-inducible genes in tumor cells. J Cancer Res Clin Oncol, 124(6), 315-20 (1998)
DOI: 10.1007/s004320050175

121. M. S. Ullah, A. J. Davies and A. P. Halestrap: The plasma membrane lactate transporter MCT4, but not MCT1, is up-regulated by hypoxia through a HIF-1alpha-dependent mechanism. J Biol Chem, 281(14), 9030-7 (2006)
DOI: 10.1074/jbc.M511397200

122. J. W. Kim, I. Tchernyshyov, G. L. Semenza and C. V. Dang: HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab, 3(3), 177-85 (2006)
DOI: 10.1016/j.cmet.2006.02.002

123. J. J. Lum, T. Bui, M. Gruber, J. D. Gordan, R. J. DeBerardinis, K. L. Covello, M. C. Simon and C. B. Thompson: The transcription factor HIF-1alpha plays a critical role in the growth factor-dependent regulation of both aerobic and anaerobic glycolysis. Genes Dev, 21(9), 1037-49 (2007)
DOI: 10.1101/gad.1529107

124. P. H. Maxwell, M. S. Wiesener, G. W. Chang, S. C. Clifford, E. C. Vaux, M. E. Cockman, C. C. Wykoff, C. W. Pugh, E. R. Maher and P. J. Ratcliffe: The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature, 399(6733), 271-5 (1999)
DOI: 10.1038/20459

125. H. Zhong, K. Chiles, D. Feldser, E. Laughner, C. Hanrahan, M. M. Georgescu, J. W. Simons and G. L. Semenza: Modulation of hypoxia-inducible factor 1alpha expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics. Cancer Res, 60(6), 1541-5 (2000)

126. Y. Kim, H. J. Nam, J. Lee, Y. Park do, C. Kim, Y. S. Yu, D. Kim, S. W. Park, J. Bhin, D. Hwang, H. Lee, G. Y. Koh and S. H. Baek: Methylation-dependent regulation of HIF-1alpha stability restricts retinal and tumour angiogenesis. Nat Commun, 7, 10347 (2016)
DOI: 10.1038/ncomms10347

127. Q. Yan, P. Chen, S. Wang, N. Liu, P. Zhao and A. Gu: Association between HIF-1alpha C1772T/G1790A polymorphisms and cancer susceptibility: an updated systematic review and meta-analysis based on 40 case-control studies. BMC Cancer, 14, 950 (2014)
DOI: 10.1186/1471-2407-14-950

128. X. Wang, Y. Liu, H. Ren, Z. Yuan, S. Li, J. Sheng, T. Zhao, Y. Chen, F. Liu, F. Wang, H. Huang and J. Hao: Polymorphisms in the hypoxia-inducible factor-1alpha gene confer susceptibility to pancreatic cancer. Cancer Biol Ther, 12(5), 383-7 (2011)
DOI: 10.4161/cbt.12.5.15982

129. S. L. Neuhausen: Ethnic differences in cancer risk resulting from genetic variation. Cancer, 86(11 Suppl), 2575-82 (1999)
DOI: 10.1002/(SICI)1097-0142(19991201)86:11+<2575::AID-CNCR15>3.0.CO;2-F

130. M. C. Hanna, C. Go, C. Roden, R. T. Jones, P. Pochanard, A. Y. Javed, A. Javed, C. Mondal, E. Palescandolo, P. Van Hummelen, C. Hatton, A. J. Bass, S. M. Chun, D. C. Na, T. I. Kim, S. J. Jang, R. U. Osarogiagbon, W. C. Hahn, M. Meyerson, L. A. Garraway and L. E. MacConaill: Colorectal cancers from distinct ancestral populations show variations in BRAF mutation frequency. PLoS One, 8(9), e74950 (2013)
DOI: 10.1371/journal.pone.0074950

131. C. I. Li, K. E. Malone and J. R. Daling: Differences in breast cancer hormone receptor status and histology by race and ethnicity among women 50 years of age and older. Cancer Epidemiol Biomarkers Prev, 11(7), 601-7 (2002)

132. M. A. de Bruin, A. Kwong, B. A. Goldstein, J. A. Lipson, D. M. Ikeda, L. McPherson, B. Sharma, A. Kardashian, E. Schackmann, K. E. Kingham, M. A. Mills, D. W. West, J. M. Ford and A. W. Kurian: Breast cancer risk factors differ between Asian and white women with BRCA1/2 mutations. Fam Cancer, 11(3), 429-39 (2012)
DOI: 10.1007/s10689-012-9531-9

133. B. J. Fuhrman, C. Schairer, M. H. Gail, J. Boyd-Morin, X. Xu, L. Y. Sue, S. S. Buys, C. Isaacs, L. K. Keefer, T. D. Veenstra, C. D. Berg, R. N. Hoover and R. G. Ziegler: Estrogen metabolism and risk of breast cancer in postmenopausal women. J Natl Cancer Inst, 104(4), 326-39 (2012)
DOI: 10.1093/jnci/djr531

134. L. Quan, C. C. Hong, G. Zirpoli, M. R. Roberts, T. Khoury, L. E. Sucheston-Campbell, D. H. Bovbjerg, L. Jandorf, K. Pawlish, G. Ciupak, W. Davis, E. V. Bandera, C. B. Ambrosone and S. Yao: Variants of estrogen-related genes and breast cancer risk in European and African American women. Endocr Relat Cancer, 21(6), 853-64 (2014)
DOI: 10.1530/ERC-14-0250

135. C. E. Steuer, M. Behera, L. Berry, S. Kim, M. Rossi, G. Sica, T. K. Owonikoko, B. E. Johnson, M. G. Kris, P. A. Bunn, F. R. Khuri, E. B. Garon and S. S. Ramalingam: Role of race in oncogenic driver prevalence and outcomes in lung adenocarcinoma: Results from the Lung Cancer Mutation Consortium. Cancer, 122(5), 766-72 (2016)
DOI: 10.1002/cncr.29812

136. T. Kohno, H. Kunitoh, K. Suzuki, S. Yamamoto, A. Kuchiba, Y. Matsuno, N. Yanagitani and J. Yokota: Association of KRAS polymorphisms with risk for lung adenocarcinoma accompanied by atypical adenomatous hyperplasias. Carcinogenesis, 29(5), 957-63 (2008)
DOI: 10.1093/carcin/bgn048

137. J. D. Hunt, A. Strimas, J. E. Martin, M. Eyer, M. Haddican, B. G. Luckett, B. Ruiz, T. W. Axelrad, W. L. Backes and E. T. Fontham: Differences in KRAS mutation spectrum in lung cancer cases between African Americans and Caucasians after occupational or environmental exposure to known carcinogens. Cancer Epidemiol Biomarkers Prev, 11(11), 1405-12 (2002)

138. M. Kang, X. J. Shen, S. Kim, F. Araujo-Perez, J. A. Galanko, C. F. Martin, R. S. Sandler and T. O. Keku: Somatic gene mutations in African Americans may predict worse outcomes in colorectal cancer. Cancer Biomark, 13(5), 359-66 (2013)

139. F. Yuan, M. Shi, J. Ji, H. Shi, C. Zhou, Y. Yu, B. Liu, Z. Zhu and J. Zhang: KRAS and DAXX/ATRX gene mutations are correlated with the clinicopathological features, advanced diseases, and poor prognosis in Chinese patients with pancreatic neuroendocrine tumors. Int J Biol Sci, 10(9), 957-65 (2014)
DOI: 10.7150/ijbs.9773

140. S. Krishnaswamy, R. Kanteti, J. S. Duke-Cohan, S. Loganathan, W. Liu, P. C. Ma, M. Sattler, P. A. Singleton, N. Ramnath, F. Innocenti, D. L. Nicolae, Z. Ouyang, J. Liang, J. Minna, M. F. Kozloff, M. K. Ferguson, V. Natarajan, Y. C. Wang, J. G. Garcia, E. E. Vokes and R. Salgia: Ethnic differences and functional analysis of MET mutations in lung cancer. Clin Cancer Res, 15(18), 5714-23 (2009)
DOI: 10.1158/1078-0432.CCR-09-0070

141. J. Bauml, R. Mick, Y. Zhang, C. D. Watt, A. Vachani, C. Aggarwal, T. Evans and C. Langer: Frequency of EGFR and KRAS mutations in patients with non small cell lung cancer by racial background: do disparities exist? Lung Cancer, 81(3), 347-53 (2013)
DOI: 10.1016/j.lungcan.2013.05.011

142. R. S. Leidner, P. Fu, B. Clifford, A. Hamdan, C. Jin, R. Eisenberg, T. J. Boggon, M. Skokan, W. A. Franklin, F. Cappuzzo, F. R. Hirsch, M. Varella-Garcia and B. Halmos: Genetic abnormalities of the EGFR pathway in African American Patients with non-small-cell lung cancer. J Clin Oncol, 27(33), 5620-6 (2009)
DOI: 10.1200/JCO.2009.23.1431

143. W. Zhang, E. B. McQuitty, R. Olsen, H. Fan, H. Hendrickson, F. O. Tio, K. Newton, P. T. Cagle and J. Jagirdar: EGFR mutations in US Hispanic versus non-Hispanic white patients with lung adenocarcinoma. Arch Pathol Lab Med, 138(4), 543-5 (2014)
DOI: 10.5858/arpa.2013-0311-OA

144. F. Buttitta, F. Barassi, G. Fresu, L. Felicioni, A. Chella, D. Paolizzi, G. Lattanzio, S. Salvatore, P. P. Camplese, S. Rosini, T. Iarussi, F. Mucilli, R. Sacco, A. Mezzetti and A. Marchetti: Mutational analysis of the HER2 gene in lung tumors from Caucasian patients: mutations are mainly present in adenocarcinomas with bronchioloalveolar features. Int J Cancer, 119(11), 2586-91 (2006)
DOI: 10.1002/ijc.22143

145. B. Gao, Y. Sun, J. Zhang, Y. Ren, R. Fang, X. Han, L. Shen, X. Y. Liu, W. Pao, H. Chen and H. Ji: Spectrum of LKB1, EGFR, and KRAS mutations in chinese lung adenocarcinomas. J Thorac Oncol, 5(8), 1130-5 (2010)
DOI: 10.1097/JTO.0b013e3181e05016

146. H. Blaszyk, C. B. Vaughn, A. Hartmann, R. M. McGovern, J. J. Schroeder, J. Cunningham, D. Schaid, S. S. Sommer and J. S. Kovach: Novel pattern of p53 gene mutations in an American black cohort with high mortality from breast cancer. Lancet, 343(8907), 1195-7 (1994)
DOI: 10.1016/S0140-6736(94)92403-1

147. K. A. Hill and S. S. Sommer: p53 as a mutagen test in breast cancer. Environ Mol Mutagen, 39(2-3), 216-27 (2002)
DOI: 10.1002/em.10065

148. G. Dong, X. He, Y. Chen, H. Cao, J. Wang, X. Liu, S. Wang, S. Wan and J. Xing: Genetic variations in genes of metabolic enzymes predict postoperational prognosis of patients with colorectal cancer. Mol Cancer, 14, 171 (2015)
DOI: 10.1186/s12943-015-0442-x

149. Y. M. Patel, S. L. Park, S. G. Carmella, V. Paiano, N. Olvera, D. O. Stram, C. A. Haiman, L. Le Marchand and S. S. Hecht: Metabolites of the Polycyclic Aromatic Hydrocarbon Phenanthrene in the Urine of Cigarette Smokers from Five Ethnic Groups with Differing Risks for Lung Cancer. PLoS One, 11(6), e0156203 (2016)
DOI: 10.1371/journal.pone.0156203

150. S. E. Murphy, S. S. Park, E. F. Thompson, L. R. Wilkens, Y. Patel, D. O. Stram and L. Le Marchand: Nicotine N-glucuronidation relative to N-oxidation and C-oxidation and UGT2B10 genotype in five ethnic/racial groups. Carcinogenesis, 35(11), 2526-33 (2014)
DOI: 10.1093/carcin/bgu191

151. A. Budhu, A. Terunuma, G. Zhang, S. P. Hussain, S. Ambs and X. W. Wang: Metabolic profiles are principally different between cancers of the liver, pancreas and breast. Int J Biol Sci, 10(9), 966-72 (2014)
DOI: 10.7150/ijbs.9810

152. L. Chen, H. Chen, Y. Li, L. Li, Y. Qiu and J. Ren: Endocannabinoid and ceramide levels are altered in patients with colorectal cancer. Oncol Rep, 34(1), 447-54 (2015)
DOI: 10.3892/or.2015.3973

153. P. Mishra and S. Ambs: Metabolic Signatures of Human Breast Cancer. Mol Cell Oncol, 2(3) (2015)
DOI: 10.4161/23723556.2014.992217

154. C. M. Rocha, J. Carrola, A. S. Barros, A. M. Gil, B. J. Goodfellow, I. M. Carreira, J. Bernardo, A. Gomes, V. Sousa, L. Carvalho and I. F. Duarte: Metabolic signatures of lung cancer in biofluids: NMR-based metabonomics of blood plasma. J Proteome Res, 10(9), 4314-24 (2011)
DOI: 10.1021/pr200550p

155. O. F. Bathe, R. Shaykhutdinov, K. Kopciuk, A. M. Weljie, A. McKay, F. R. Sutherland, E. Dixon, N. Dunse, D. Sotiropoulos and H. J. Vogel: Feasibility of identifying pancreatic cancer based on serum metabolomics. Cancer Epidemiol Biomarkers Prev, 20(1), 140-7 (2011)
DOI: 10.1158/1055-9965.EPI-10-0712

156. I. M. Di Gangi, T. Mazza, A. Fontana, M. Copetti, C. Fusilli, A. Ippolito, F. Mattivi, A. Latiano, A. Andriulli, U. Vrhovsek and V. Pazienza: Metabolomic profile in pancreatic cancer patients: a consensus-based approach to identify highly discriminating metabolites. Oncotarget, 7(5), 5815-29 (2016)

157. S. A. Ritchie, H. Akita, I. Takemasa, H. Eguchi, E. Pastural, H. Nagano, M. Monden, Y. Doki, M. Mori, W. Jin, T. T. Sajobi, D. Jayasinghe, B. Chitou, Y. Yamazaki, T. White and D. B. Goodenowe: Metabolic system alterations in pancreatic cancer patient serum: potential for early detection. BMC Cancer, 13, 416 (2013)
DOI: 10.1186/1471-2407-13-416

158. A. Daemen, D. Peterson, N. Sahu, R. McCord, X. Du, B. Liu, K. Kowanetz, R. Hong, J. Moffat, M. Gao, A. Boudreau, R. Mroue, L. Corson, T. O’Brien, J. Qing, D. Sampath, M. Merchant, R. Yauch, G. Manning, J. Settleman, G. Hatzivassiliou and M. Evangelista: Metabolite profiling stratifies pancreatic ductal adenocarcinomas into subtypes with distinct sensitivities to metabolic inhibitors. Proc Natl Acad Sci U S A, 112(32), E4410-7 (2015)
DOI: 10.1073/pnas.1501605112

159. L. Gao, Z. Wen, C. Wu, T. Wen and C. N. Ong: Metabolic profiling of plasma from benign and malignant pulmonary nodules patients using mass spectrometry-based metabolomics. Metabolites, 3(3), 539-51 (2013)
DOI: 10.3390/metabo3030539

160. C. M. Rocha, A. S. Barros, B. J. Goodfellow, I. M. Carreira, A. Gomes, V. Sousa, J. Bernardo, L. Carvalho, A. M. Gil and I. F. Duarte: NMR metabolomics of human lung tumours reveals distinct metabolic signatures for adenocarcinoma and squamous cell carcinoma. Carcinogenesis, 36(1), 68-75 (2015)
DOI: 10.1093/carcin/bgu226

161. E. Marien, M. Meister, T. Muley, S. Fieuws, S. Bordel, R. Derua, J. Spraggins, R. Van de Plas, J. Dehairs, J. Wouters, M. Bagadi, H. Dienemann, M. Thomas, P. A. Schnabel, R. M. Caprioli, E. Waelkens and J. V. Swinnen: Non-small cell lung cancer is characterized by dramatic changes in phospholipid profiles. Int J Cancer, 137(7), 1539-48 (2015)
DOI: 10.1002/ijc.29517

162. F. Farshidfar, A. M. Weljie, K. Kopciuk, W. D. Buie, A. Maclean, E. Dixon, F. R. Sutherland, A. Molckovsky, H. J. Vogel and O. F. Bathe: Serum metabolomic profile as a means to distinguish stage of colorectal cancer. Genome Med, 4(5), 42 (2012)
DOI: 10.1186/gm341

163. S. J. Schnitt: Classification and prognosis of invasive breast cancer: from morphology to molecular taxonomy. Mod Pathol, 23 Suppl 2, S60-4 (2010)
DOI: 10.1038/modpathol.2010.33

164. M. D. Cao, S. Lamichhane, S. Lundgren, A. Bofin, H. Fjosne, G. F. Giskeodegard and T. F. Bathen: Metabolic characterization of triple negative breast cancer. BMC Cancer, 14, 941 (2014)
DOI: 10.1186/1471-2407-14-941

165. J. Budczies, S. F. Brockmoller, B. M. Muller, D. K. Barupal, C. Richter-Ehrenstein, A. Kleine-Tebbe, J. L. Griffin, M. Oresic, M. Dietel, C. Denkert and O. Fiehn: Comparative metabolomics of estrogen receptor positive and estrogen receptor negative breast cancer: alterations in glutamine and beta-alanine metabolism. J Proteomics, 94, 279-88 (2013)
DOI: 10.1016/j.jprot.2013.10.002

166. L. A. Sturtz, J. Melley, K. Mamula, C. D. Shriver and R. E. Ellsworth: Outcome disparities in African American women with triple negative breast cancer: a comparison of epidemiological and molecular factors between African American and Caucasian women with triple negative breast cancer. BMC Cancer, 14, 62 (2014)
DOI: 10.1186/1471-2407-14-62

167. L. Brunelli, E. Caiola, M. Marabese, M. Broggini and R. Pastorelli: Capturing the metabolomic diversity of KRAS mutants in non-small-cell lung cancer cells. Oncotarget, 5(13), 4722-31 (2014)
DOI: 10.18632/oncotarget.1958

168. C. Gieger, L. Geistlinger, E. Altmaier, M. Hrabe de Angelis, F. Kronenberg, T. Meitinger, H. W. Mewes, H. E. Wichmann, K. M. Weinberger, J. Adamski, T. Illig and K. Suhre: Genetics meets metabolomics: a genome-wide association study of metabolite profiles in human serum. PLoS Genet, 4(11), e1000282 (2008)
DOI: 10.1371/journal.pgen.1000282

169. J. Shen, L. Yan, S. Liu, C. B. Ambrosone and H. Zhao: Plasma metabolomic profiles in breast cancer patients and healthy controls: by race and tumor receptor subtypes. Transl Oncol, 6(6), 757-65 (2013)
DOI: 10.1593/tlo.13619

170. L. Jing, L. Su and B. Z. Ring: Ethnic background and genetic variation in the evaluation of cancer risk: a systematic review. PLoS One, 9(6), e97522 (2014)
DOI: 10.1371/journal.pone.0097522

171. N. J. Ollberding, A. M. Nomura, L. R. Wilkens, B. E. Henderson and L. N. Kolonel: Racial/ethnic differences in colorectal cancer risk: the multiethnic cohort study. Int J Cancer, 129(8), 1899-906 (2011)
DOI: 10.1002/ijc.25822

172. E. Taioli, S. Benhamou, C. Bouchardy, I. Cascorbi, N. Cajas-Salazar, H. Dally, K. M. Fong, J. E. Larsen, L. Le Marchand, S. J. London, A. Risch, M. R. Spitz, I. Stucker, B. Weinshenker, X. Wu and P. Yang: Myeloperoxidase G-463A polymorphism and lung cancer: a HuGE genetic susceptibility to environmental carcinogens pooled analysis. Genet Med, 9(2), 67-73 (2007)
DOI: 10.1097/GIM.0b013e31803068b1

173. H. Dally, K. Gassner, B. Jager, P. Schmezer, B. Spiegelhalder, L. Edler, P. Drings, H. Dienemann, V. Schulz, K. Kayser, H. Bartsch and A. Risch: Myeloperoxidase (MPO) genotype and lung cancer histologic types: the MPO -463 A allele is associated with reduced risk for small cell lung cancer in smokers. Int J Cancer, 102(5), 530-5 (2002)
DOI: 10.1002/ijc.10756

174. J. L. Wright, I. M. Reis, W. Zhao, J. E. Panoff, C. Takita, V. Sujoy, C. R. Gomez, M. Jorda, D. Franceschi and J. Hurley: Racial disparity in estrogen receptor positive breast cancer patients receiving trimodality therapy. Breast, 21(3), 276-83 (2012)
DOI: 10.1016/j.breast.2011.11.003

175. W. Lee, A. C. Lockhart, R. B. Kim and M. L. Rothenberg: Cancer pharmacogenomics: powerful tools in cancer chemotherapy and drug development. Oncologist, 10(2), 104-11 (2005)
DOI: 10.1634/theoncologist.10-2-104

176. F. Wu, J. Zhang, N. Hu, H. Wang, T. Xu, Y. Liu and Y. Zheng: Effect of hENT1 polymorphism G-706C on clinical outcomes of gemcitabine-containing chemotherapy for Chinese non-small-cell lung cancer patients. Cancer Epidemiol, 38(6), 728-32 (2014)
DOI: 10.1016/j.canep.2014.08.008

177. A. Romero-Lorca, A. Novillo, M. Gaibar, F. Bandres and A. Fernandez-Santander: Impacts of the Glucuronidase Genotypes UGT1A4, UGT2B7, UGT2B15 and UGT2B17 on Tamoxifen Metabolism in Breast Cancer Patients. PLoS One, 10(7), e0132269 (2015)
DOI: 10.1371/journal.pone.0132269

178. T. Efferth and M. Volm: Pharmacogenetics for individualized cancer chemotherapy. Pharmacol Ther, 107(2), 155-76 (2005)
DOI: 10.1016/j.pharmthera.2005.02.005

179. A. J. Pommier, M. Farren, B. Patel, M. Wappett, F. Michopoulos, N. R. Smith, J. Kendrew, J. Frith, R. Huby, C. Eberlein, H. Campbell, C. Womack, P. D. Smith, J. Robertson, S. Morgan, S. E. Critchlow and S. T. Barry: Leptin, BMI, and a Metabolic Gene Expression Signature Associated with Clinical Outcome to VEGF Inhibition in Colorectal Cancer. Cell Metab, 23(1), 77-93 (2016)
DOI: 10.1016/j.cmet.2015.10.015

180. H. H. Yoon, Q. Shi, S. R. Alberts, R. M. Goldberg, S. N. Thibodeau, D. J. Sargent, F. A. Sinicrope and O. Alliance for Clinical Trials in: Racial Differences in BRAF/KRAS Mutation Rates and Survival in Stage III Colon Cancer Patients. J Natl Cancer Inst, 107(10) (2015)
DOI: 10.1093/jnci/djv186

181. P. K. Paik, M. E. Arcila, M. Fara, C. S. Sima, V. A. Miller, M. G. Kris, M. Ladanyi and G. J. Riely: Clinical characteristics of patients with lung adenocarcinomas harboring BRAF mutations. J Clin Oncol, 29(15), 2046-51 (2011)
DOI: 10.1200/JCO.2010.33.1280

182. Z. Li, X. W. Liu, Z. C. Chi, B. S. Sun, Y. Cheng and L. W. Cheng: Detection of K-ras Mutations in Predicting Efficacy of Epidermal Growth Factor Receptor Tyrosine Kinase (EGFR-TK) Inhibitor in Patients with Metastatic Colorectal Cancer. PLoS One, 10(5), e0101019 (2015)
DOI: 10.1371/journal.pone.0101019

183. W. Zhou and D. C. Christiani: East meets West: ethnic differences in epidemiology and clinical behaviors of lung cancer between East Asians and Caucasians. Chin J Cancer, 30(5), 287-92 (2011)
DOI: 10.5732/cjc.011.10106

184. J. M. Reinersman, M. L. Johnson, G. J. Riely, D. A. Chitale, A. D. Nicastri, G. A. Soff, A. G. Schwartz, C. S. Sima, G. Ayalew, C. Lau, M. F. Zakowski, V. W. Rusch, M. Ladanyi and M. G. Kris: Frequency of EGFR and KRAS mutations in lung adenocarcinomas in African Americans. J Thorac Oncol, 6(1), 28-31 (2011)
DOI: 10.1097/JTO.0b013e3181fb4fe2

185. H. Linardou, I. J. Dahabreh, D. Kanaloupiti, F. Siannis, D. Bafaloukos, P. Kosmidis, C. A. Papadimitriou and S. Murray: Assessment of somatic k-RAS mutations as a mechanism associated with resistance to EGFR-targeted agents: a systematic review and meta-analysis of studies in advanced non-small-cell lung cancer and metastatic colorectal cancer. Lancet Oncol, 9(10), 962-72 (2008)
DOI: 10.1016/S1470-2045(08)70206-7

186. C. Mao, L. X. Qiu, R. Y. Liao, F. B. Du, H. Ding, W. C. Yang, J. Li and Q. Chen: KRAS mutations and resistance to EGFR-TKIs treatment in patients with non-small cell lung cancer: a meta-analysis of 22 studies. Lung Cancer, 69(3), 272-8 (2010)
DOI: 10.1016/j.lungcan.2009.11.020

187. A. Terunuma, N. Putluri, P. Mishra, E. A. Mathe, T. H. Dorsey, M. Yi, T. A. Wallace, H. J. Issaq, M. Zhou, J. K. Killian, H. S. Stevenson, E. D. Karoly, K. Chan, S. Samanta, D. Prieto, T. Y. Hsu, S. J. Kurley, V. Putluri, R. Sonavane, D. C. Edelman, J. Wulff, A. M. Starks, Y. Yang, R. A. Kittles, H. G. Yfantis, D. H. Lee, O. B. Ioffe, R. Schiff, R. M. Stephens, P. S. Meltzer, T. D. Veenstra, T. F. Westbrook, A. Sreekumar and S. Ambs: MYC-driven accumulation of 2-hydroxyglutarate is associated with breast cancer prognosis. J Clin Invest, 124(1), 398-412 (2014)
DOI: 10.1172/JCI71180

188. S. A. Tishkoff and B. C. Verrelli: Patterns of human genetic diversity: implications for human evolutionary history and disease. Annu Rev Genomics Hum Genet, 4, 293-340 (2003)
DOI: 10.1146/annurev.genom.4.070802.110226

189. S. H. Zahm and J. F. Fraumeni, Jr.: Racial, ethnic, and gender variations in cancer risk: considerations for future epidemiologic research. Environ Health Perspect, 103 Suppl 8, 283-6 (1995)
DOI: 10.2307/3432326
DOI: 10.1289/ehp.95103s8283

190. N. L. Pernick, F. H. Sarkar, P. A. Philip, P. Arlauskas, A. F. Shields, V. K. Vaitkevicius, M. C. Dugan and N. V. Adsay: Clinicopathologic analysis of pancreatic adenocarcinoma in African Americans and Caucasians. Pancreas, 26(1), 28-32 (2003)
DOI: 10.1097/00006676-200301000-00006

Key Words: Cancer, Metabolism, Race, Ethnic, Mutation, Oncogene, Tumor suppressor, Oncometabolite

Send correspondence to: Pankaj K. Singh, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, 985950 Nebraska Medical Center, Omaha, NE 68198-5950, Tel: 402-559-2726, Fax: 402-559-2813, E-mail: pankaj.singh@unmc.edu