Integrative Analysis of Dysfunctional Modules Driven by Genomic Alterations at System Level Across 11 Cancer Types

Author(s): Yin Wang, Zhenhao Liu, Baofeng Lian*, Lei Liu*, Lu Xie*

Journal Name: Combinatorial Chemistry & High Throughput Screening
Accelerated Technologies for Biotechnology, Bioassays, Medicinal Chemistry and Natural Products Research

Volume 21 , Issue 10 , 2018

Become EABM
Become Reviewer
Call for Editor


Aim and Objective: Integrating multi-omics data to identify driver genes and key biological functions for tumorigenesis remains a major challenge.

Method: A new computational pipeline was developed to identify the Driver Mutation-Differential Co-Expression (DM-DCE) modules based on dysfunctional networks across 11 TCGA cancers.

Results: Functional analyses provided insight into the properties of various cancers, and found common cellular signals / pathways of cancers. Furthermore, the corresponding network analysis identified conservations or interactions across different types of cancers, thus the crosstalk between the key signaling pathways, immunity and cancers was found. Clinical analysis also identified key prognostic / survival patterns.

Conclusion: Taken together, our study sheds light on both cancer-specific and cross-cancer characteristics systematically.

Keywords: Cancer, network analysis, cancer corresponding, Driver Mutation to Differential Co-expression, diagnosis, cellular signals.

Podlaha, O.; Riester, M.; De, S.; Michor, F. Evolution of the cancer genome. Trends Genet., 2012, 28, 155-163.
Yang, Y.; Han, L.; Yuan, Y.; Li, J.; Hei, N.; Liang, H. Gene co-expression network analysis reveals common system level properties of prognostic genes across cancer types. Nat. Commun., 2014, 5, 3231.
International Cancer Genome Consortium; Hudson, T.J.; Anderson, W.; Artez, A.; Barker, A.D.; Bell, C.; Bernabé, R.R.; Bhan, M.K.; Calvo, F.; Eerola, I.; Gerhard, D.S.; Guttmacher, A.; Guyer, M.; Hemsley, F.M.; Jennings, J.L.; Kerr, D.; Klatt, P.; Kolar, P.; Kusada, J.; Lane, D.P.; Laplace, F.; Youyong, L.; Nettekoven, G.; Ozenberger, B.; Peterson, J.; Rao, T.S.; Remacle, J.; Schafer, A.J.; Shibata, T.; Stratton, M.R.; Vockley, J.G.; Watanabe, K.; Yang, H.; Yuen, M.M.; Knoppers, B.M.; Bobrow, M.; Cambon-Thomsen, A.; Dressler, L.G.; Dyke, S.O.; Joly, Y.; Kato, K.; Kennedy, K.L.; Nicolás, P.; Parker, M.J.; Rial-Sebbag, E.; Romeo-Casabona, C.M.; Shaw, K.M.; Wallace, S.; Wiesner, G.L.; Zeps, N.; Lichter, P.; Biankin, A.V.; Chabannon, C.; Chin, L.; Clément, B.; de Alava, E.; Degos, F.; Ferguson, ML.; Geary, P.; Hayes, D.N.; Hudson, T.J.; Johns, A.L.; Kasprzyk, A.; Nakagawa, H.; Penny, R.; Piris, M.A.; Sarin, R.; Scarpa, A.; Shibata, T.; van de Vijver, M.; Futreal, P.A.; Aburatani, H.; Bayés, M.; Botwell, D.D.; Campbell, P.J.; Estivill, X.; Gerhard, D.S.; Grimmond, S.M.; Gut, I.; Hirst, M.; López-Otín, C.; Majumder, P.; Marra, M.; McPherson, J.D.; Nakagawa, H.; Ning, Z.; Puente, X.S.; Ruan, Y.; Shibata, T.; Stratton, M.R.; Stunnenberg, H.G.; Swerdlow, H.; Velculescu, V.E.; Wilson, R.K.; Xue, H.H.; Yang, L.; Spellman, P.T.; Bader, G.D.; Boutros, P.C.; Campbell, P.J.; Flicek, P.; Getz, G.; Guigó, R.; Guo, G.; Haussler, D.; Heath, S.; Hubbard, T.J.; Jiang, T.; Jones, S.M.; Li, Q.; López- Bigas, N.; Luo, R.; Muthuswamy, L.; Ouellette, B.F.; Pearson, J.V.; Puente, X.S.; Quesada, V.; Raphael, B.J.; Sander, C.; Shibata, T.; Speed, T.P.; Stein, L.D.; Stuart, J.M.; Teague, J.W.; Totoki, Y.; Tsunoda, T.; Valencia, A.; Wheeler, D.A.; Wu, H.; Zhao, S.; Zhou, G.; Stein, L.D.; Guigó, R.; Hubbard, T.J.; Joly, Y.; Jones, S.M.; Kasprzyk, A.; Lathrop, M.; López-Bigas, N.; Ouellette, B.F.; Spellman, P.T.; Teague, J.W.; Thomas, G.; Valencia, A.; Yoshida, T.; Kennedy, K.L.; Axton, M.; Dyke, S.O.; Futreal, P.A.; Gerhard, D.S.; Gunter, C.; Guyer, M.; Hudson, T.J.; McPherson, J.D.; Miller, L.J.; Ozenberger, B.; Shaw, K.M.; Kasprzyk, A.; Stein, L.D.; Zhang, J.; Haider, S.A.; Wang, J.; Yung, C.K.; Cros, A.; Liang, Y.; Gnaneshan, S.; Guberman, J.; Hsu, J.; Bobrow, M.; Chalmers, D.R.; Hasel, K.W.; Joly, Y.; Kaan, T.S.; Kennedy, K.L.; Knoppers, B.M.; Lowrance, W.W.; Masui, T.; Nicolás, P.; Rial-Sebbag, E.; Rodriguez, L.L.; Vergely, C.; Yoshida, T.; Grimmond, S.M.; Biankin, A.V.; Bowtell, D.D.; Cloonan, N.; DeFazio, A.; Eshleman, J.R.; Etemadmoghadam, D.; Gardiner, B.B.; Kench, J.G.; Scarpa, A.; Sutherland, R.L.; Tempero, M.A.; Waddell, N.J.; Wilson, P.J.; McPherson, J.D.; Gallinger, S.; Tsao, M.S.; Shaw, P.A.; Petersen, G.M.; Mukhopadhyay, D.; Chin, L.; DePinho, R.A.; Thayer, S.; Muthuswamy, L.; Shazand, K.; Beck, T.; Sam, M.; Timms, L.; Ballin, V.; Lu, Y.; Ji, J.; Zhang, X.; Chen, F.; Hu, X.; Zhou, G.; Yang, Q.; Tian, G.; Zhang, L.; Xing, X.; Li, X.; Zhu, Z.; Yu, Y.; Yu, J.; Yang, H.; Lathrop, M.; Tost, J.; Brennan, P.; Holcatova, I.; Zaridze, D.; Brazma, A.; Egevard, L.; Prokhortchouk, E.; Banks, R.E.; Uhlén, M.; Cambon-Thomsen, A.; Viksna, J.; Ponten, F.; Skryabin, K.; Stratton, M.R.; Futreal, P.A.; Birney, E.; Borg, A.; Børresen-Dale, A.L.; Caldas, C.; Foekens, J.A.; Martin, S.; Reis- Filho, J.S.; Richardson, A.L.; Sotiriou, C.; Stunnenberg, H.G.; Thoms, G.; van de Vijver, M.; van't Veer, L.; Calvo, F.; Birnbaum, D.; Blanche, H.; Boucher, P.; Boyault, S.; Chabannon, C.; Gut, I.; Masson-Jacquemier, J.D.; Lathrop, M.; Pauporté, I.; Pivot, X.; Vincent-Salomon, A.; Tabone, E.; Theillet, C.; Thomas, G.; Tost, J.; Treilleux, I.; Calvo, F.; Bioulac-Sage, P.; Clément, B.; Decaens, T.; Degos, F.; Franco, D.; Gut, I.; Gut, M.; Heath, S.; Lathrop, M.; Samuel, D.; Thomas, G.; Zucman-Rossi, J.; Lichter, P.; Eils, R.; Brors, B.; Korbel, J.O.; Korshunov, A.; Landgraf, P.; Lehrach, H.; Pfister, S.; Radlwimmer, B.; Reifenberger, G.; Taylor, M.D.; von Kalle, C.; Majumder, P.P.; Sarin, R.; Rao, T.S.; Bhan, M.K.; Scarpa, A.; Pederzoli, P.; Lawlor, R.A.; Delledonne, M.; Bardelli, A.; Biankin, A.V.; Grimmond, S.M.; Gress, T.; Klimstra, D.; Zamboni, G.; Shibata, T.; Nakamura, Y.; Nakagawa, H.; Kusada, J.; Tsunoda, T.; Miyano, S.; Aburatani, H.; Kato, K.; Fujimoto, A.; Yoshida, T.; Campo, E.; López-Otín, C.; Estivill, X.; Guigó, R.; de Sanjosé, S.; Piris, M.A.; Montserrat, E.; González-Díaz, M.; Puente, X.S.; Jares, P.; Valencia, A.; Himmelbauer, H.; Quesada, V.; Bea, S.; Stratton, M.R.; Futreal, P.A.; Campbell, P.J.; Vincent-Salomon, A.; Richardson, A.L.; Reis-Filho, J.S.; van de Vijver, M.; Thomas, G.; Masson-Jacquemier, J.D.; Aparicio, S.; Borg, A.; Børresen- Dale, A.L.; Caldas, C.; Foekens, J.A.; Stunnenberg, H.G.; van't Veer, L.; Easton, D.F.; Spellman, P.T.; Martin, S.; Barker, A.D.; Chin, L.; Collins, F.S.; Compton, C.C.; Ferguson, M.L.; Gerhard, D.S.; Getz, G.; Gunter, C.; Guttmacher, A.; Guyer, M.; Hayes, D.N.; Lander, E.S.; Ozenberger, B.; Penny, R.; Peterson, J.; Sander, C.; Shaw, K.M.; Speed, T.P.; Spellman, P.T.; Vockley, J.G.; Wheeler, D.A.; Wilson, R.K.; Hudson, T.J.; Chin, L.; Knoppers, B.M.; Lander, E.S.; Lichter, P.; Stein, L.D.; Stratton, M.R.; Anderson, W.; Barker, A.D.; Bell, C.; Bobrow, M.; Burke, W.; Collins, F.S.; Compton, C.C.; DePinho, R.A.; Easton, D.F.; Futreal, P.A.; Gerhard, D.S.; Green, A.R.; Guyer, M.; Hamilton, S.R.; Hubbard, T.J.; Kallioniemi, O.P.; Kennedy, K.L.; Ley, T.J.; Liu, E.T.; Lu, Y.; Majumder, P.; Marra, M.; Ozenberger, B.; Peterson, J.; Schafer, A.J.; Spellman, P.T.; Stunnenberg, H.G.; Wainwright, B.J.; Wilson, R.K.; Yang, H. International network of cancer genome projects. Nature, 2010. 464(7291), 993-998
Vogelstein, B.; Papadopoulos, N.; Velculescu, V.E.; Zhou, S.; Diaz, L.A. Jr, Kinzler, K.W. Cancer genome landscapes. Science, 2013, 339, 1546-1558.
De la Fuente, A. From ‘differential expression’ to ‘differential networking’ - identification of dysfunctional regulatory networks in diseases. Trends Genet., 2010, 26(7), 326-333.
Brown, C.D.; Mangravite, L.M.; Engelhardt, B.E. Integrative modeling of eQTLs and Cis-regulatory elements suggests mechanisms underlying cell type specificity of eQTLs. PLoS Genet., 2013, 9(8), e1003649.
Cho, D-Y.; Kim, Y-A.; Przytycka, T.M. Chapter 5: Network Biology Approach to Complex Diseases. PLOS Comput. Biol., 2012, 8(12), e1002820.
Liu, Z.; Zhang, S. Toward a systematic understanding of cancers: A survey of the pan-cancer study. Front. Genet., 2014, 5, 194.
Peng, L.; Bian, X.W.; Li, D.K.; Xu, C.; Wang, G.M.; Xia, Q.Y.; Xiong, Q. Large-scale RNA-Seq transcriptome analysis of 4043 cancers and 548 normal tissue controls across 12 TCGA cancer types. Sci. Rep., 2015, 5, 13413.
Ung, M.H.; Liu, C.C.; Cheng, C. Integrative analysis of cancer genes in a functional interactome. Sci. Rep., 2016, 6, 29228.
Ali, I.; Haque, A.; Saleem, K.; Hsieh, M.F. Curcumin-I Knoevenagel’s condensates and their Schiff’s bases as anticancer agents: Synthesis, pharmacological and simulation studies. Bioorg. Med. Chem., 2013, 21(13), 3808-3820.
Ali, I.; Lone, M.N.; Alothman, Z.A.; Alwarthan, A. Insights into the pharmacology of new heterocycles embedded with oxopyrrolidine rings: DNA binding, molecular docking, and anticancer studies. J. Mol. Liq., 2017, 234, 391-402.
Basheer, A.A. Chemical chiral pollution: Impact on the society and science and need of the regulations in the 21st century. Chirality,20B18, 30(4), 402-406.
Foloppe, N.; Chen, I-J. Towards understanding the unbound state of drug compounds: Implications for the intramolecular reorganization energy upon binding. Bioorg. Med. Chem., 2016, 24(10), 2159-2189.
Liu, Z.P.; Wang, Y.; Wen, T.; Zhang, X-S.; Xia, W.; Chen, L. Dynamically Dysfunctional Protein Interactions in the Development of Alzheimer’s Disease. San Antonio, TX, USA11-14 Oct. 2009IEEE International Conference on Systems, Man and Cybernetics, 2009.
Hwang, D.; Rust, A.G.; Ramsey, S.; Smith, J.J.; Leslie, D.M.; Weston, A.D.; de Atauri, P.; Aitchison, J.D.; Hood, L.; Siegel, A.F.; Bolouri, H. A data integration methodologyfor systems biology. Proc. Natl. Acad. Sci. USA, 2005, 102(48), 17296-17301.
Ruan, J.; Dean, A.K.; Zhang, W. A general co-expression network-based approach to gene expression analysis: comparison and applications. BMC Syst. Biol., 2014, 4, 8.
Cheng, W.; Zhang, X.; Guo, Z.; Shi, Y.; Wang, W. Graph-regularized dual Lasso for robust eQTL mapping. Bioinformatics, 2014, 30(12), i139-i148.
Bashashati, A.; Haffari, G.; Ding, J.; Ha, G.; Lui, K.; Rosner, J.; Huntsman, D.G.; Caldas, C.; Aparicio, S.A.; Shah, S.P. DriverNet: uncovering the impact of somatic driver mutations on transcriptional networks in cancer. Genome Biol., 2012, 13, R124.
Subramanian, A.; Tamayo, P.; Mootha, V.K.; Mukherjee, S.; Ebert, B.L.; Gillette, M.A.; Paulovich, A.; Pomeroy, S.L.; Golub, T.R.; Lander, E.S.; Mesirov, J.P. Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl. Acad. Sci. USA, 2005, 102(43), 15545-15550.
Gasper, G.; Rahman, M. Basic Hypergeometric Series., Cambridge, UK; New York: Cambridge University Press. xxvi, p. 428.
Benjamini, Y.; Hochberg, Y. Controlling the false discovery rate: A practical and powerful approach to multiple testing. J. R. Stat. Soc., 1995, 57, 289-300.
Marsaglia, G.; Tsang, W.; Wang, J. Evaluating Kolmogorov’s Distribution. J. Stat. Softw., 2003, 8.
Law, V.; Knox, C.; Djoumbou, Y.; Jewison, T.; Guo, A.C.; Liu, Y.; Maciejewski, A.; Arndt, D.; Wilson, M.; Neveu, V.; Tang, A.; Gabriel, G.; Ly, C.; Adamjee, S.; Dame, Z.T.; Han, B.; Zhou, Y.; Wishart, D.S. DrugBank 4.0: shedding new light on drug metabolism. Nucleic Acids Res., 2014, 42(1), D1091-D1097.
Cheng, F.; Liu, C.; Lin, C.C.; Zhao, J.; Jia, P.; Li, W.H.; Zhao, Z. A gene gravity model for the evolution of cancer genomes: A study of 3,000 cancer genomes across 9 cancer types. PLOS Comput. Biol., 2015, 11(9), e1004497.
Golubovskaya, V.M. Focal adhesion kinase as a cancer therapy target. Anticancer. Agents Med. Chem., 2010, 10(10), 735-741.
Multhaupt, H.A.; Leitinger, B.; Gullberg, D.; Couchman, J.R. Extracellular matrix component signaling in cancer. Adv. Drug Deliv. Rev., 2016, 97, 28-40.
Schreiber, G.; Walter, M.R. Cytokine receptor interactions as drug targets. Curr. Opin. Chem. Biol., 2010, 14(4), 511-519.
Abraham, J.; Balbo, S.; Crabb, D.; Brooks, P.J. Alcohol Metabolism in Human Cells Causes DNA Damage and Activates the Fanconi Anemia-Breast Cancer Susceptibility (FA-BRCA) DNA Damage Response Network. Alcohol. Clin. Exp. Res., 2011, 35(12), 2113-2120.
Lockhart, A.C.; Tirona, R.G.; Kim, R.B. Pharmacogenetics of ATP-binding cassette transporters in cancer and chemotherapy. Mol. Cancer Ther., 2003, 2(7), 685-698.
Badawy, A.A. Tryptophan Metabolism and the Hepatic Kynurenine Pathway in Health and Disease. In:Targeting the Broadly Pathogenic Kynurenine Pathway; Mittal, S., Ed.; Springer International Publishing, 2015, pp. 11-30.
Klement, R.J.; Kämmerer, U. Is there a role for carbohydrate restriction in the treatment and prevention of cancer? Nutr. Metab. (Lond.), 2011, 8, 75.
Hur, H.; Paik, M.J.; Xuan, Y.; Nguyen, D.T.; Ham, I.H.; Yun, J.; Cho, Y.K.; Lee, G.; Han, S.U. Quantitative measurement of organic acids in tissues from gastric cancer patients indicates increased glucose metabolism in gastric cancer. PLoS One, 2014, 9(6), e98581.
Locasale, J.W. Serine, glycine and one-carbon units: cancer metabolism in full. Nat. Rev. Cancer, 2013, 13, 572-583.
Currie, E.; Schulze, A.; Zechner, R.; Walther, T.C.; Farese, R.V. Jr. Cellular fatty acid metabolism and cancer. Cell Metab., 2013, 18(2), 153-161.
Ibrahim-Hashim, A.; Wojtkowiak, J.W.; de Lourdes Coelho Ribeiro, M.; Estrella, V.; Bailey, K.M.; Cornnell, H.H.; Gatenby, R.A.; Gillies, R.J. Free base lysine increases survival and reduces metastasis in prostate cancer model. J. Cancer Sci. Ther., 2011. Suppl 1(4), JCST-S1-004.
Simpson, W.G. The calcium channel blocker verapamil and cancer chemotherapy. Cell Calcium, 1985, 6(6), 449-467.
Stuart, J.M.; Segal, E.; Koller, D.; Kim, S.K. A gene-coexpression network for global discovery of conserved genetic modules. Science, 2003, 302, 249-255.

open access plus

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2018
Published on: 21 January, 2019
Page: [771 - 783]
Pages: 13
DOI: 10.2174/1386207322666190122110726

Article Metrics

PDF: 59
HTML: 16