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Oncogenic Signaling Pathways in The Cancer Genome Atlas
Open accessAbstract
Genetic alterations in signaling pathways that control cell-cycle progression, apoptosis, and cell growth are common hallmarks of cancer, but the extent, mechanisms, and co-occurrence of alterations in these pathways differ between individual tumors and tumor types. Using mutations, copy-number changes, mRNA expression, gene fusions and DNA methylation in 9,125 tumors profiled by The Cancer Genome Atlas (TCGA), we analyzed the mechanisms and patterns of somatic alterations in ten canonical pathways: cell cycle, Hippo, Myc, Notch, Nrf2, PI-3-Kinase/Akt, RTK-RAS, TGFβ signaling, p53 and β-catenin/Wnt. We charted the detailed landscape of pathway alterations in 33 cancer types, stratified into 64 subtypes, and identified patterns of co-occurrence and mutual exclusivity. Eighty-nine percent of tumors had at least one driver alteration in these pathways, and 57% percent of tumors had at least one alteration potentially targetable by currently available drugs. Thirty percent of tumors had multiple targetable alterations, indicating opportunities for combination therapy.
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“Kirsten rat sarcoma viral oncogene homolog (KRAS) is the most frequently mutated oncogene in various types of human cancers such as pancreatic, lung, and colorectal cancer, with G12, G13, and Q61 being the most prevalent mutant codons observed (1, 2).”
From YAP/TAZ mediates resistance to KRAS inhibitors through inhibiting proapoptosis and activating the SLC7A5/mTOR axis (2024) · cites this paper as [1]
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“KRAS mutations lead to the accumulation of active GTP-bound KRAS, which in turn regulates multiple oncogenic cellular processes through its downstream mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways (1, 2).”
From YAP/TAZ mediates resistance to KRAS inhibitors through inhibiting proapoptosis and activating the SLC7A5/mTOR axis (2024) · cites this paper as [1]
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“Despite their genetic complexity, these sarcomas share genomic alterations causing PI3K/Akt/mTOR and MAPK pathway activation”
From Targeting eIF4A-dependent translation in genetically complex sarcoma (2026) · cites this paper as [7]
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“KRAS is one of the most frequently mutated oncogenes in cancer, yet efforts to directly target KRAS have been mostly unsuccessful because initial analyses of KRAS proteins indicated that they lack a clear pocket to which small molecules can bind with high affinity [1, 2].”
From Anti-tumor efficacy of a potent and selective non-covalent KRASG12D inhibitor (2022) · cites this paper as [1]
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“The Hippo pathway gene set was separated into oncogenes or tumor suppressors as previously categorized (7).”
From Targeting eIF4A-dependent translation in genetically complex sarcoma (2026) · cites this paper as [7]
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“we developed a mechanistic model integrating signaling modules reflecting the canonical human ERBB, RAS, and PI3K-AKT signaling pathways (Sanchez-Vega et al., 2018), as well as regulation of the transcription factors (TFs) MYC and AP1 (Wierling et al., 2015) (Figure 1A).”
From Efficient Parameter Estimation Enables the Prediction of Drug Response Using a Mechanistic Pan-Cancer Pathway Model (2018) · cites this paper as Sanchez-Vega et al., 2018
In the citing paper
“Amongst these are four canonical mutations – KRAS (~85%), TP53 (60–70%), CDKN2A (>50%), and SMAD4 (~50%).”
From KRAS mutation in pancreatic cancer (2021) · cites this paper as [53]
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“The disease involves deregulation of P53 and cell cycle signalling pathways1, 2, 3, 4.”
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Self-citation
Metadata
- Authors
- Sanchez-Vega, F., Mina, M., Armenia, J., Chatila, W. K., Luna, A., La, K. C., Dimitriadoy, S., Liu, D. L., Kantheti, H. S., Saghafinia, S., Chakravarty, D., Daian, F., Gao, Q., Bailey, M. H., Liang, W.-W., Foltz, S. M., Shmulevich, I., Ding, L., Heins, Z., Ochoa, A., Gross, B., Gao, J., Zhang, H., Kundra, R., Kandoth, C., Bahceci, I., Dervishi, L., Dogrusoz, U., Zhou, W., Shen, H., Laird, P. W., Way, G. P., Greene, C. S., Liang, H., Xiao, Y., Wang, C., Iavarone, A., Berger, A. H., Bivona, T. G., Lazar, A. J., Hammer, G. D., Giordano, T., Kwong, L. N., McArthur, G., Huang, C., Tward, A. D., Frederick, M. J., McCormick, F., Meyerson, M., Caesar-Johnson, S. J., Demchok, J. A., Felau, I., Kasapi, M., Ferguson, M. L., Hutter, C. M., Sofia, H. J., Tarnuzzer, R., Wang, Z., Yang, L., Zenklusen, J. C., Zhang, J. (., Chudamani, S., Liu, J., Lolla, L., Naresh, R., Pihl, T., Sun, Q., Wan, Y., Wu, Y., Cho, J., DeFreitas, T., Frazer, S., Gehlenborg, N., Getz, G., Heiman, D. I., Kim, J., Lawrence, M. S., Lin, P., Meier, S., Noble, M. S., Saksena, G., Voet, D., Zhang, H., Bernard, B., Chambwe, N., Dhankani, V., Knijnenburg, T., Kramer, R., Leinonen, K., Liu, Y., Miller, M., Reynolds, S., Shmulevich, I., Thorsson, V., Zhang, W., Akbani, R., Broom, B. M., Hegde, A. M., Ju, Z., Kanchi, R. S., Korkut, A., Li, J., Liang, H., Ling, S., Liu, W., Lu, Y., Mills, G. B., Ng, K.-S., Rao, A., Ryan, M., Wang, J., Weinstein, J. N., Zhang, J., Abeshouse, A., Armenia, J., Chakravarty, D., Chatila, W. K., de Bruijn, I., Gao, J., Gross, B. E., Heins, Z. J., Kundra, R., La, K., Ladanyi, M., Luna, A., Nissan, M. G., Ochoa, A., Phillips, S. M., Reznik, E., Sanchez-Vega, F., Sander, C., Schultz, N., Sheridan, R., Sumer, S. O., Sun, Y., Taylor, B. S., Wang, J., Zhang, H., Anur, P., Peto, M., Spellman, P., Benz, C., Stuart, J. M., Wong, C. K., Yau, C., Hayes, D. N., Parker, J. S., Wilkerson, M. D., Ally, A., Balasundaram, M., Bowlby, R., Brooks, D., Carlsen, R., Chuah, E., Dhalla, N., Holt, R., Jones, S. J. M., Kasaian, K., Lee, D., Ma, Y., Marra, M. A., Mayo, M., Moore, R. A., Mungall, A. J., Mungall, K., Robertson, A. G., Sadeghi, S., Schein, J. E., Sipahimalani, P., Tam, A., Thiessen, N., Tse, K., Wong, T., Berger, A. C., Beroukhim, R., Cherniack, A. D., Cibulskis, C., Gabriel, S. B., Gao, G. F., Ha, G., Meyerson, M., Schumacher, S. E., Shih, J., Kucherlapati, M. H., Kucherlapati, R. S., Baylin, S., Cope, L., Danilova, L., Bootwalla, M. S., Lai, P. H., Maglinte, D. T., Van Den Berg, D. J., Weisenberger, D. J., Auman, J. T., Balu, S., Bodenheimer, T., Fan, C., Hoadley, K. A., Hoyle, A. P., Jefferys, S. R., Jones, C. D., Meng, S., Mieczkowski, P. A., Mose, L. E., Perou, A. H., Perou, C. M., Roach, J., Shi, Y., Simons, J. V., Skelly, T., Soloway, M. G., Tan, D., Veluvolu, U., Fan, H., Hinoue, T., Laird, P. W., Shen, H., Zhou, W., Bellair, M., Chang, K., Covington, K., Creighton, C. J., Dinh, H., Doddapaneni, H., Donehower, L. A., Drummond, J., Gibbs, R. A., Glenn, R., Hale, W., Han, Y., Hu, J., Korchina, V., Lee, S., Lewis, L., Li, W., Liu, X., Morgan, M., Morton, D., Muzny, D., Santibanez, J., Sheth, M., Shinbrot, E., Wang, L., Wang, M., Wheeler, D. A., Xi, L., Zhao, F., Hess, J., Appelbaum, E. L., Bailey, M., Cordes, M. G., Ding, L., Fronick, C. C., Fulton, L. A., Fulton, R. S., Kandoth, C., Mardis, E. R., McLellan, M. D., Miller, C. A., Schmidt, H. K., Wilson, R. K., Crain, D., Curley, E., Gardner, J., Lau, K., Mallery, D., Morris, S., Paulauskis, J., Penny, R., Shelton, C., Shelton, T., Sherman, M., Thompson, E., Yena, P., Bowen, J., Gastier-Foster, J. M., Gerken, M., Leraas, K. M., Lichtenberg, T. M., Ramirez, N. C., Wise, L., Zmuda, E., Corcoran, N., Costello, T., Hovens, C., Carvalho, A. L., de Carvalho, A. C., Fregnani, J. H., Longatto-Filho, A., Reis, R. 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- Affiliations
- SIB Swiss Institute of Bioinformatics (CH)
- Princeton University (US)
- Broad Institute (US)
- The University of Texas at Dallas (US)
- Memorial Sloan Kettering Cancer Center (US)
- Washington University in St. Louis (US)
- Bilkent University (TR)
- University of Pennsylvania (US)
- Tesaro (United States) (US)
- Mayo Clinic (US)
- Columbia University Irving Medical Center (US)
- Fred Hutch Cancer Center (US)
- University of California, San Francisco (US)
- University of Michigan (US)
- The University of Texas MD Anderson Cancer Center (US)
- The University of Melbourne (AU)
- Baylor College of Medicine (US)
- Corresponding author
- Ciriello, Giovanni
- ORCID
- Mina, Marco
- Dimitriadoy, Sofia
- Liu, David L.
- Kantheti, Havish S.
- Saghafinia, Sadegh
- Gao, Qingsong
- Liang, Wen-Wei
- Foltz, Steven M.
- Dervishi, Leonard
- Way, Gregory P.
- Greene, Casey S.
- Xiao, Yonghong
- Wang, Chen
- Iavarone, Antonio
- Berger, Alice H.
- Bivona, Trever G.
- Hammer, Gary D.
- Kwong, Lawrence N.
- McArthur, Grant
- Huang, Chenfei
- Tward, Aaron D.
- Frederick, Mitchell J.
- McCormick, Frank
- Felau, Ina
- Kasapi, Melpomeni
- Ferguson, Martin L.
- Sofia, Heidi J.
- Tarnuzzer, Roy
- Yang, Liming
- Zenklusen, Jean C.
- Zhang, Jiashan (Julia)
- Liu, Jia
- Pihl, Todd
- Sun, Qiang
- Wu, Ye
- Gehlenborg, Nils
- Getz, Gad
- Heiman, David I.
- Kim, Jaegil
- Lawrence, Michael S.
- Lin, Pei
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- Kelley, Robin K.
- Landen, Charles N.
- Prados, Michael
- VandenBerg, Scott
- Roggin, Kevin
- Kendler, Ady
- Steele, Ruth
- Jimeno, Antonio
- Forgie, Ian
- Mannelli, Massimo
- Carney, Michael
- Campos, Benito
- Unterberg, Andreas
- Bossler, Aaron
- Ma, Deqin
- Milhem, Mohammed
- Godwin, Andrew K.
- Madan, Rashna
- Adebamowo, Clement
- Adebamowo, Sally N.
- Boussioutas, Alex
- Beer, David
- Bocklage, Therese
- Landrum, Lisa
- Moxley, Katherine
- Zuna, Rosemary
- Feldman, Michael
- Dhir, Rajiv
- Luketich, James
- Carlotti, Carlos Gilberto
- Kemp, Rafael
- Tirapelli, Daniela
- Catto, James
- Swisher, Elizabeth
- Creaney, Jenette
- Robinson, Bruce
- Shelley, Carl Simon
- Bradford, Carol
- Carey, Thomas
- Prince, Mark
- Rozek, Laura
- Wolf, Gregory
- Fong, Kwun M.
- Yang, Ian
- Rathmell, W. Kimryn
- Kovatich, Albert J.
- Shriver, Craig D.
- DiPersio, John
- Drake, Bettina
- Govindan, Ramaswamy
- Heath, Sharon
- Ley, Timothy
- Rubin, Mark A.
- Lee, Jung Il
- Aredes, Natália D.
- Mariamidze, Armaz
- Ciriello, Giovanni
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2018-04
- Volume
- 173
- Issue
- 2
- Pages
- 321-337.e10
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC6070353
- OpenAlex
- W2796153225
- Cited by
- 3,201
- References
- 82
- Citations by year
- 2026: 249 · 2025: 387 · 2024: 414 · 2023: 521 · 2022: 472 · 2021: 502 · 2020: 353 · 2019: 229 · 2018: 68
- FWCI
- 89.54
- Type
- journal article
- Language
- en
- Open access
- hybrid
- dx.doi.org
- Licence
- Locations
- Cell (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- SERVAL (Université de Lausanne) (publishedVersion, other-oa)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Bilkent University Institutional Repository (Bilkent University) (submittedVersion, other-oa)
- IRIS (submittedVersion)
- UWA Profiles and Research Repository (UWA) (submittedVersion, cc-by-nc-nd)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- Bern Open Repository and Information System (University of Bern) (submittedVersion, cc-by-nc-nd)
- Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
- Florence Research (University of Florence) (submittedVersion, cc-by-nc-nd)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion, cc-by-nc-nd)
- mediaTUM (Technical University of Munich) (submittedVersion, other-oa)
- Bilkent University Institutional Repository (Bilkent University) (submittedVersion)
- Institutional Research Information System University of Ferrara (University of Ferrara) (submittedVersion, cc-by-nc-nd)
- Spiral (Imperial College London) (submittedVersion, cc-by-nc-nd)
- Open Access CRIS of the University of Bern
- Funders
- NIH (U54 HG003273, U54 HG003067, U54 HG003079, U24 CA143799, U24 CA143835, U24 CA143840, U24 CA143843, U24 CA143845, U24 CA143848, U24 CA143858, U24 CA143866, U24 CA143867, U24 CA143882, U24 CA143883, U24 CA144025, P30 CA016672)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- oncogenic signaling, somatic alterations, driver mutations, copy number alterations, gene fusion, DNA methylation, cell cycle, Hippo signaling pathway, c-Myc, Notch signaling, Nrf2, PI3K/Akt signaling, TGF-beta signaling, p53, tumor subtypes, combination therapy, TCGA
- MeSH terms
- Humans, Neoplasms, Signal Transduction, Tumor Suppressor Protein p53, Transforming Growth Factor beta, Phosphatidylinositol 3-Kinases, Databases, Genetic, Wnt Proteins, Genes, Neoplasm
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