Skip to main content Accessibility help

Symmetry in cancer networks identified: Proposal for multicancer biomarkers

  • Pramod Shinde (a1), Loïc Marrec (a2), Aparna Rai (a1), Alok Yadav (a3), Rajesh Kumar (a4), Mikhail Ivanchenko (a5), Alexey Zaikin (a5) (a6) (a7) and Sarika Jalan (a1) (a3) (a5)...


One of the most challenging problems in biomedicine and genomics is the identification of disease biomarkers. In this study, proteomics data from seven major cancers were used to construct two weighted protein–protein interaction networks, i.e., one for the normal and another for the cancer conditions. We developed rigorous, yet mathematically simple, methodology based on the degeneracy at –1 eigenvalues to identify structural symmetry or motif structures in network. Utilizing eigenvectors corresponding to degenerate eigenvalues in the weighted adjacency matrix, we identified structural symmetry in underlying weighted protein–protein interaction networks constructed using seven cancer data. Functional assessment of proteins forming these structural symmetry exhibited the property of cancer hallmarks. Survival analysis refined further this protein list proposing BMI, MAPK11, DDIT4, CDKN2A, and FYN as putative multicancer biomarkers. The combined framework of networks and spectral graph theory developed here can be applied to identify symmetrical patterns in other disease networks to predict proteins as potential disease biomarkers.


Corresponding author

*Corresponding author. Email:


Hide All
Agrawal, A., Sarkar, C., Dwivedi, S. K., Dhasmana, N., & Jalan, S. (2014). Quantifying randomness in protein-protein interaction networks of different species: A random matrix approach. Physica A, 404, 359367.
Aguirre-Gamboa, R., Gomez-Rueda, H., Martnez-Ledesma, E., Martnez-Torteya, A., Chacolla-Huaringa, R., Rodriguez-Barrientos, A., … Trevino, V. (2013). SurvExpress: An online biomarker validation tool and database for cancer gene expression data using survival analysis. PloS One, 8(9), 74250.
Ahn, J., Yoon, Y., Park, C., Shin, E., & Park, S. (2011). Integrative gene network construction for predicting a set of complementary prostate cancer genes. Bioinformatics, 27(13), 18461853.
Albert, R., & Barabási, AL. (2002). Statistical mechanics of complex networks. Review of Modern Physics, 74(1), 47.
Barabasi, A. L., & Otavi, Z. N. (2004). Network biology: Understanding the cells functional organization. Nature Review Genetics, 5, 101113.
Barh, D., Carpi, A., Verma, M., & Gunduz, M. (2014). Cancer biomarkers: Minimal and noninvasive early diagnosis and prognosis. Florida, USA: CRC Press.
Brandes, U. (2008). On variants of shortest-path betweenness centrality and their generic computation. Social Networks, 30(2), 136145.
Brockmoller, S. F., Bucher, E., Muller, B. M., Budczies, J., Hilvo, M., Griffin, J. L., … Darb-Esfahani, S. (2011). Integration of metabolomics and expression of Glycerol-3-phosphate Acyltransferase (GPAM) in breast cancer link to patient survival, hormone receptor status, and metabolic profiling. Journal of Proteome Research, 11(2), 850860.
Cubuk, C., Hidalgo, M. R., Amadoz, A., Pujana, M. A., Mateo, F., Herranz, C., … Dopazo, J. (2018). Gene expression integration into pathway modules reveals a pan-cancer metabolic landscape. Cancer Research, 78(21), 60596072.
Cheng, F., Chuang, L., Bairong, S., & Zhongming, Z. (2016). Investigating cellular network heterogeneity and modularity in cancer: A network entropy and unbalanced motif approach. BMC Systems Biology, 10(3), 65.
Chiang, G. G., & Abraham, R. T. (2007). Targeting the mTOR signaling network in cancer. Trends in Molecular Medicine, 13(10), 433442.
Chung, F., Linyuan, L., & Van, V. (2003). Spectra of random graphs with given expected degrees. Proceedings of the National Academy of Sciences, 100, 63136318.
Cragg, J. G., & Donald, S. G. (1997). Inferring the rank of a matrix. Journal of Economics, 76(1), 223250.
Dixit, A., Yi, L., Gowthaman, R., Torkamani, A., Schork, N.J. & Verkhivker, G.M. (2009). Sequence and structure signatures of cancer mutation hotspots in protein kinases. PloS One, 4(10), e7485.
Elias, D., & Ditzel, H. J. (2015). Fyn is an important molecule in cancer pathogenesis and drug resistance. Pharmacological Research, 100, 250254.
Figshare data:
Folador, E. L., de Carvalho, P. V., Silva, W. M., Ferreira, R. S., Silva, A., Gromiha, M., … Röttger, R. (2016). In silico identification of essential proteins in Corynebacterium pseudotuberculosis based on protein-protein interaction networks. BMC Systems Biology, 10(1), 103.
Fox, A. D., Hescott, B. J., Blumer, A. C., & Slonim, D. K. (2011). Connectedness of PPI network neighborhoods identifies regulatory hub proteins. Bioinformatics, 27(8), 11351142.
Furlong, L. I. (2013). Human diseases through the lens of network biology. Trends in Genetics, 29(3), 150159.
Hanahan, D., & Weinberg, R. A. (2011). Hallmarks of cancer: The next generation. Cell, 144(5), 646674.
He, Z., He, J., Liu, Z., Xu, J., Sofia, F. Y., Liu, H., & Yang, J. (2014). MAPK11 in breast cancer cells enhances osteoclastogenesis and bone resorption. Biochimie, 106, 2432.
Jalan, S., Ung, C. Y., Bhojwani, J., Li, B., Zhang, L., Lan, S. H., & Gong, Z. (2012). Spectral analysis of gene co-expression network of Zebrafish. EPL, 99(4), 48004.
Kim, M. S., Kim, J. R., Kim, D., Lander, A. D., & Cho, K. H. (2012). Spatiotemporal network motif reveals the biological traits of developmental gene regulatory networks in Drosophila melanogaster. BMC Systems Biology, 6(1), 31.
Krause, A. E., Frank, K. A., Mason, D. M., Ulanowicz, R. E., & Taylor, W. W. (2003). Compartments revealed in food-web structure. Nature, 426(6964), 282285.
Lage, K., Karlberg, E. O., Stø rling, Z. M., Olason, P. I., Pedersen, A. G., Rigina, O., … Moreau, Y. (2007). A human phenome-interactome network of protein complexes implicated in genetic disorders. Nature Biotechnology, 25(3), 309.
Liberzon, A., Subramanian, A., Pinchback, R., Thorvaldsdóttir, H., Tamayo, P., & Mesirov, J. P. (2011). Molecular signatures database (MSigDB) 3.0. Bioinformatics, 27(12), 17391740.
Marrec, L., & Jalan, S. (2017). Analysing degeneracies in networks spectra. EPL, 117(4), 48001.
Mi, H., Lazareva-Ulitsky, B., Loo, R., Kejariwal, A., Vandergriff, J., Rabkin, S., … Kitano, H. (2005). The PANTHER database of protein families, subfamilies, functions and pathways. Nucleic Acids Research, 33, D284D288.
Milo, R., Itzkovitz, S., Kashtan, N., Levitt, R., Shen-Orr, S., Ayzenshtat, I., … Alon, U. (2004). Superfamilies of evolved and designed networks. Science, 303(5663), 15381542.
Nacerddine, K., Beaudry, J. B., Ginjala, V., Westerman, B., Mattiroli, F., Song, J. Y., … Zevenhoven, J. (2012). Akt-mediated phosphorylation of Bmi1 modulates its oncogenic potential, E3 ligase activity, and DNA damage repair activity in mouse prostate cancer. Journal of Clinical Investigation, 122(5), 1920.
Ocone, A. & Sanguinetti, G. (2011). Reconstructing transcription factor activities in hierarchical transcription network motifs. Bioinformatics, 27(20), 28732879.
Perrault, R., Wang, H., Wang, M., Rosidi, B. & Iliakis, G. (2004). Backup pathways of NHEJ are suppressed by DNAPK. Journal of Cellular Biochemistry, 92(4), 781794.
Pinto, J. A., Rolfo, C., Raez, L. E., Prado, A., Araujo, J. M., Bravo, L., … Mas, L. A. (2017). In silico evaluation of DNA Damage Inducible Transcript 4 gene (DDIT4) as prognostic biomarker in several malignancies. Scientific Reports, 7, article number 1526.
Potestio, R., Caccioli, F., & Vivo, P. (2009). Random matrix approach to collective behavior and bulk universality in protein dynamics. Physical Review Letters, 103(26), 268101.
Rai, A., Menon, A. V., & Jalan, S. (2014). Randomness and preserved patterns in cancer network. Scientific Reports, 4, 6368.
Rai, A., Pawar, A. K., & Jalan, S. (2015). Prognostic interaction patterns in diabetes mellitus II: A random-matrix-theory relation. Physical Review E, 92(2), 022806.
Rai, A., Shinde, P. & Jalan, S. (2018). Network spectra for drug-target identification in complex diseases: New guns against old foes. Applied Network Science, 3(1), 51.
Sarkar, C., & Jalan, S. (2017). Complex networks: An emerging branch of science. Physics News, 47, 34, and references therein.
Sarkar, C., & Jalan, S. (2018). Spectral properties of complex networks. Chaos, 28(10), 102101, and references therein.
Saramäki, J., Kivel, ä M., Onnela, J. P., Kaski, K., & Kertész, J. (2007). Generalizations of the clustering coefficient to weighted complex networks, Physical Review E, 75, 027105.
Shinde, P., Yadav, A., Rai, A., & Jalan, S. (2015). Dissortativity and duplications in oral cancer. European Physical Journal B, 88(8), 197.
Shinde, P., & Jalan, S. (2015). A multilayer protein-protein interaction network analysis of different life stages in Caenorhabditis elegans. EPL, 112(5), 58001.
Shinde, P., Sarkar, C., & Jalan, S. (2018). Codon based co-occurrence network motifs in human mitochondria. Scientific Reports, 8(1), 3060.
Shinde, P., Whitwell, H. J., Verma, R. K., Zaikin, A. & Jalan, S. (2018). Impact of mitochondrial epistatic interactions on evolution of different human subpopulations. BioRxiv, 505818.
Stratton, M. R., Campbell, P. J., & Futreal, P. A. (2009). The cancer genome. Nature, 458, 719724.
Szklarczyk, D., Franceschini, A., Wyder, S., Forslund, K., Heller, D., Huerta-Cepas, J., … Kuhn, M. (2014). STRING v10: Protein-Protein interaction networks, integrated over the tree of life. Nucleic Acids Research, 43, D447D452.
Teichmann, S. A., & Babu, M. M. (2004). Gene regulatory network growth by duplication. Nature genetics, 36(5), 492.
Ushioda, R., Hoseki, J. & Nagata, K. (2013). Glycosylation-independent ERAD pathway serves as a backup system under ER stress. Molecular Biology of the Cell, 24(20), 31553163.
Van Mieghem, P. (2010). Graph spectra for complex networks. New York, USA: Cambridge University Press.
Wang, J., Huang, Y., Wu, F. X., & Pan, Y. (2012). Symmetry compression method for discovering network motifs. IEEE/ACM Transactions on Computational Biology and Bioinformatics, 9(6), 17761789.
Winter, D. L., Erce, M. A., & Wilkins, M. R. (2014). A web of possibilities: Network-based discovery of protein interaction codes. Journal of Proteome Research, 13(12), 53335338.
Yadav, A. & Jalan, S. (2015). Origin and implications of zero degeneracy in networks spectra. Chaos: An Interdisciplinary Journal of Nonlinear Science, 25(4), 043110.
Yixuan, Y., Kiat, L. S., Yee, C. L., Huiyin, L., Yunhao, C., Kuan, C. P., … Pin, L. Y. (2010). Cathepsin S mediates gastric cancer cell migration and invasion via a putative network of metastasis-associated proteins. Journal of Proteome Research, 9(9), 47674778.
Yu, X., Li, Z., & Shen, J. (2016). BRD7: A novel tumor suppressor gene in different cancers. American Journal of Translational Research, 8(2), 742.
Zack, T. I., Schumacher, S. E., Carter, S. L., Cherniack, A. D., Saksena, G., Tabak, B., … Sougnez, C. (2013). Pan-cancer patterns of somatic copy number alteration. Nature Genetics, 45(10), 1134.


Type Description Title
Supplementary materials

Shinde et al. supplementary material
Shinde et al. supplementary material

 PDF (7.1 MB)
7.1 MB

Symmetry in cancer networks identified: Proposal for multicancer biomarkers

  • Pramod Shinde (a1), Loïc Marrec (a2), Aparna Rai (a1), Alok Yadav (a3), Rajesh Kumar (a4), Mikhail Ivanchenko (a5), Alexey Zaikin (a5) (a6) (a7) and Sarika Jalan (a1) (a3) (a5)...


Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed