Abstract
Identifying genes that are capable of inducing tumorigenesis has been a major challenge in cancer research. In many cases, such genes frequently show somatic mutations in tumor samples; thus various computational methods for predicting cancer genes have been developed based on “significantly mutated genes.” However, this approach is intrinsically limited by the fact that there are many cancer genes infrequently mutated in cancer genomes. Therefore, we recently developed MUFFINN (Mutations For Functional Impact on Network Neighbors), a method for cancer gene prediction based not only on mutation occurrences in each gene but also those of neighbors in functional networks. This enables the identification of cancer genes with infrequent mutation occurrence. We demonstrated that MUFFINN could retrieve known cancer genes more efficiently than gene-based methods and predicted cancer genes with low mutation occurrences in tumor samples. Users can freely access a web server (http://www.inetbio.org/muffinn) and run predictions with either public or private data of cancer somatic mutations. For given information of mutation occurrence profiles, the MUFFINN server returns lists of candidate cancer genes by four distinct predictions with different combinations between gene networks and scoring algorithms. Stand-alone software is also available, which allows MUFFINN to be run on local machines with a custom gene network. Here, we present an overall guideline for using the MUFFINN web server and stand-alone software for the discovery of novel cancer genes.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA Jr, Kinzler KW (2013) Cancer genome landscapes. Science 339(6127):1546–1558. https://doi.org/10.1126/science.1235122
Dees ND, Zhang Q, Kandoth C, Wendl MC, Schierding W, Koboldt DC, Mooney TB, Callaway MB, Dooling D, Mardis ER, Wilson RK, Ding L (2012) MuSiC: identifying mutational significance in cancer genomes. Genome Res 22(8):1589–1598. https://doi.org/10.1101/gr.134635.111
Tomczak K, Czerwinska P, Wiznerowicz M (2015) The Cancer Genome Atlas (TCGA): an immeasurable source of knowledge. Contemp Oncol (Pozn) 19(1A):A68–A77. https://doi.org/10.5114/wo.2014.47136
Zhang J, Baran J, Cros A, Guberman JM, Haider S, Hsu J, Liang Y, Rivkin E, Wang J, Whitty B, Wong-Erasmus M, Yao L, Kasprzyk A (2011) International Cancer Genome Consortium Data Portal—a one-stop shop for cancer genomics data. Database (Oxford) 2011:bar026. doi:https://doi.org/10.1093/database/bar026
Stratton MR, Campbell PJ, Futreal PA (2009) The cancer genome. Nature 458(7239):719–724. https://doi.org/10.1038/nature07943
Lawrence MS, Stojanov P, Polak P, Kryukov GV, Cibulskis K, Sivachenko A, Carter SL, Stewart C, Mermel CH, Roberts SA, Kiezun A, Hammerman PS, McKenna A, Drier Y, Zou L, Ramos AH, Pugh TJ, Stransky N, Helman E, Kim J, Sougnez C, Ambrogio L, Nickerson E, Shefler E, Cortes ML, Auclair D, Saksena G, Voet D, Noble M, DiCara D, Lin P, Lichtenstein L, Heiman DI, Fennell T, Imielinski M, Hernandez B, Hodis E, Baca S, Dulak AM, Lohr J, Landau DA, Wu CJ, Melendez-Zajgla J, Hidalgo-Miranda A, Koren A, McCarroll SA, Mora J, Crompton B, Onofrio R, Parkin M, Winckler W, Ardlie K, Gabriel SB, Roberts CWM, Biegel JA, Stegmaier K, Bass AJ, Garraway LA, Meyerson M, Golub TR, Gordenin DA, Sunyaev S, Lander ES, Getz G (2013) Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 499(7457):214–218. https://doi.org/10.1038/nature12213
Reva B, Antipin Y, Sander C (2007) Determinants of protein function revealed by combinatorial entropy optimization. Genome Biol 8(11):R232. https://doi.org/10.1186/gb-2007-8-11-r232
Wood LD, Parsons DW, Jones S, Lin J, Sjoblom T, Leary RJ, Shen D, Boca SM, Barber T, Ptak J, Silliman N, Szabo S, Dezso Z, Ustyanksky V, Nikolskaya T, Nikolsky Y, Karchin R, Wilson PA, Kaminker JS, Zhang Z, Croshaw R, Willis J, Dawson D, Shipitsin M, Willson JK, Sukumar S, Polyak K, Park BH, Pethiyagoda CL, Pant PV, Ballinger DG, Sparks AB, Hartigan J, Smith DR, Suh E, Papadopoulos N, Buckhaults P, Markowitz SD, Parmigiani G, Kinzler KW, Velculescu VE, Vogelstein B (2007) The genomic landscapes of human breast and colorectal cancers. Science 318(5853):1108–1113. https://doi.org/10.1126/science.1145720
Cho A, Shim JE, Kim E, Supek F, Lehner B, Lee I (2016) MUFFINN: cancer gene discovery via network analysis of somatic mutation data. Genome Biol 17(1):129. https://doi.org/10.1186/s13059-016-0989-x
Lee I, Blom UM, Wang PI, Shim JE, Marcotte EM (2011) Prioritizing candidate disease genes by network-based boosting of genome-wide association data. Genome Res 21(7):1109–1121. https://doi.org/10.1101/gr.118992.110
Szklarczyk D, Franceschini A, Wyder S, Forslund K, Heller D, Huerta-Cepas J, Simonovic M, Roth A, Santos A, Tsafou KP, Kuhn M, Bork P, Jensen LJ, von Mering C (2015) STRING v10: protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res 43(Database issue):D447–D452. https://doi.org/10.1093/nar/gku1003
Farrell CM, O’Leary NA, Harte RA, Loveland JE, Wilming LG, Wallin C, Diekhans M, Barrell D, Searle SM, Aken B, Hiatt SM, Frankish A, Suner MM, Rajput B, Steward CA, Brown GR, Bennett R, Murphy M, Wu W, Kay MP, Hart J, Rajan J, Weber J, Snow C, Riddick LD, Hunt T, Webb D, Thomas M, Tamez P, Rangwala SH, McGarvey KM, Pujar S, Shkeda A, Mudge JM, Gonzalez JM, Gilbert JG, Trevanion SJ, Baertsch R, Harrow JL, Hubbard T, Ostell JM, Haussler D, Pruitt KD (2014) Current status and new features of the Consensus Coding Sequence database. Nucleic Acids Res 42(Database issue):D865–D872. https://doi.org/10.1093/nar/gkt1059
Zhu H, Yu JJ (2010) Gene expression patterns in the histopathological classification of epithelial ovarian cancer. Exp Ther Med 1(1):187–192. https://doi.org/10.3892/etm_00000030
Gasco M, Shami S, Crook T (2002) The p53 pathway in breast cancer. Breast Cancer Res 4(2):70–76
Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, Tavtigian S, Liu Q, Cochran C, Bennett LM, Ding W et al (1994) A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266(5182):66–71
Bryan EJ, Jokubaitis VJ, Chamberlain NL, Baxter SW, Dawson E, Choong DY, Campbell IG (2002) Mutation analysis of EP300 in colon, breast and ovarian carcinomas. Int J Cancer 102(2):137–141. https://doi.org/10.1002/ijc.10682
Futreal PA, Coin L, Marshall M, Down T, Hubbard T, Wooster R, Rahman N, Stratton MR (2004) A census of human cancer genes. Nat Rev Cancer 4(3):177–183. https://doi.org/10.1038/nrc1299
Tamborero D, Gonzalez-Perez A, Perez-Llamas C, Deu-Pons J, Kandoth C, Reimand J, Lawrence MS, Getz G, Bader GD, Ding L, Lopez-Bigas N (2013) Comprehensive identification of mutational cancer driver genes across 12 tumor types. Sci Rep 3:2650. https://doi.org/10.1038/srep02650
Mann KM, Ward JM, Yew CC, Kovochich A, Dawson DW, Black MA, Brett BT, Sheetz TE, Dupuy AJ, Australian Pancreatic Cancer Genome I, Chang DK, Biankin AV, Waddell N, Kassahn KS, Grimmond SM, Rust AG, Adams DJ, Jenkins NA, Copeland NG (2012) Sleeping Beauty mutagenesis reveals cooperating mutations and pathways in pancreatic adenocarcinoma. Proc Natl Acad Sci U S A 109(16):5934–5941. https://doi.org/10.1073/pnas.1202490109
March HN, Rust AG, Wright NA, ten Hoeve J, de Ridder J, Eldridge M, van der Weyden L, Berns A, Gadiot J, Uren A, Kemp R, Arends MJ, Wessels LF, Winton DJ, Adams DJ (2011) Insertional mutagenesis identifies multiple networks of cooperating genes driving intestinal tumorigenesis. Nat Genet 43(12):1202–1209. https://doi.org/10.1038/ng.990
Ekyalongo RC, Yee D (2017) Revisiting the IGF-1R as a breast cancer target. NPJ Precis Oncol 1. https://doi.org/10.1038/s41698-017-0017-y
Moore-Smith L, Pasche B (2011) TGFBR1 signaling and breast cancer. J Mammary Gland Biol Neoplasia 16(2):89–95. https://doi.org/10.1007/s10911-011-9216-2
Liu ZJ, Semenza GL, Zhang HF (2015) Hypoxia-inducible factor 1 and breast cancer metastasis. J Zhejiang Univ Sci B 16(1):32–43. https://doi.org/10.1631/jzus.B1400221
Branham MT, Marzese DM, Laurito SR, Gago FE, Orozco JI, Tello OM, Vargas-Roig LM, Roque M (2012) Methylation profile of triple-negative breast carcinomas. Oncogene 1:e17. https://doi.org/10.1038/oncsis.2012.17
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2019 Springer Science+Business Media, LLC, part of Springer Nature
About this protocol
Cite this protocol
Han, H., Lehner, B., Lee, I. (2019). Cancer Gene Discovery by Network Analysis of Somatic Mutations Using the MUFFINN Server. In: Starr, T. (eds) Cancer Driver Genes. Methods in Molecular Biology, vol 1907. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-8967-6_3
Download citation
DOI: https://doi.org/10.1007/978-1-4939-8967-6_3
Published:
Publisher Name: Humana Press, New York, NY
Print ISBN: 978-1-4939-8966-9
Online ISBN: 978-1-4939-8967-6
eBook Packages: Springer Protocols