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Cancer Genome Evolution Research Group
Group Leader:听Dr Nicholas McGranahan听
Research
The cancer genome contains within it an archaeological record about its past, with each genomic event representing a scar from the mutational processes that have been active during a tumour鈥檚 life history.听
The advent of next-generation sequencing, coupled with its exponential cost decrease, has led to the sequencing of exomes and entire cancer genomes at a large-scale. Indeed, consortia such as听听(the Cancer Genome Atlas) and听(the International Cancer Genome Consortium) have made thousands of sequenced cancer genomes and exomes publicly available.听
To date, this data has been used to reveal many of the key genomic events involved in cancer, distinguishing key driver and passenger mutations (Lawrence et al., 2014), as well as shedding light on some of the key mutational processes shaping cancer evolution (Alexandrov et al., 2013). However, we have learned less than initially anticipated from these sequencing projects, and targeted therapies that have focused on established driver events have not appreciably improved cancer patients鈥� overall survival times.听
Tumour heterogeneity
A primary obstacle to success of personalized medicine is intra-tumour heterogeneity (McGranahan and Swanton (2015)). Recent work from us and others have demonstrated not only that the genomic landscape of each tumour is unique but also even different regions of the same tumour can be vastly divergent (Burrell et al., 2013). This intra-tumour heterogeneity is likely a key cause of drug resistance and therapeutic failure.听
While intra-tumour heterogeneity may confound treatment success, it can also serve to illuminate the evolutionary history of tumours (Greaves, 2015; McGranahan and Swanton, 2015).
Bioinformatics
We utilize state-of-the-art bioinformatics and evolutionary methods to decipher cancer genome evolution and to explore patterns of tumour growth and development across cancers, focussing on lung cancer. Ultimately, we aim to gain a deeper understanding of the rules that govern tumour evolution and anti-tumour immunity to improve patient treatment. 听
Computational tools
We recently developed a novel 听to enable exploration of T cell content in DNA sequencing data.Another听example of a bioinformatics tool we have recently developed to understand immune escape, is听,听Loss听Of听Heterozygosity in听Human听Leukocyte听Antigen.听LOHHLA is available at听.
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Selected publications
- Bentham R, Litchfield K, Watkins TBK, Lim EL, Rosenthal R, Mart铆nez-Ruiz C, Hiley CT, Bakir MA, Salgado R, Moore DA, Jamal-Hanjani M; TRACERx Consortium, Swanton C, McGranahan N#. . Nature. 2021 Sep;597(7877):555-560. doi: 10.1038/s41586-021-03894-5. Epub 2021 Sep 8. PMID: 34497419.
听 - Black JRM, McGranahan N. . Nat Rev Cancer. 2021 Jun;21(6):379-392. doi:10.1038/s41568-021-00336-2. Epub 2021 Mar 16. PMID: 3372769
听 - Hernando B, Dietzen M, Parra G, Gil-Barrachina M, Pitarch G, Mahiques L,Valcuende-Cavero F, McGranahan N#, Martinez-Cadenas C. . 2021 Mar;32(3):412-421. doi: 10.1016/j.annonc.2020.11.023. Epub 2020. Dec 8. PMID: 33307203.
听 - Litchfield K, Reading JL, Puttick C, Thakkar K, Abbosh C, Bentham R, WatkinsTBK, Rosenthal R, Biswas D, Rowan A, Lim E, Al Bakir M, Turati V, Guerra-Assun莽茫o JA, Conde L, Furness AJS, Saini SK, Hadrup SR, Herrero J, Lee SH, VanLoo P, Enver T, Larkin J, Hellmann MD, Turajlic S, Quezada SA, McGranahan N#,Swanton C. . Cell. 2021 Feb 4;184(3):596-614.e14.doi: 10.1016/j.cell.2021.01.002. Epub 2021 Jan 27. PMID: 33508232; PMCID:PMC7933824.
听 - Schenk A, L贸pez S, Kschischo M, McGranahan N. . Evol Appl. 2020 Apr 17;13(7):1550-1557. doi: 10.1111/eva.12964.
听 - Watkins TBK, Lim EL, Petkovic M, Elizalde S, Birkbak NJ, Wilson GA, Moore DA, Gr枚nroos E, Rowan A, Dewhurst SM, Demeulemeester J, Dentro SC, Horswell S, Au L,Haase K, Escudero M, Rosenthal R, Bakir MA, Xu H, Litchfield K, Lu WT, Mourikis TP, Dietzen M, Spain L, Cresswell GD, Biswas D, Lamy P, Nordentoft I, Harbst K, Castro-Giner F, Yates LR, Caramia F, Jaulin F, Vicier C, Tomlinson IPM, Brastianos PK, Cho RJ, Bastian BC, Dyrskj酶t L, J枚nsson GB, Savas P, Loi S, Campbell PJ, Andre F, Luscombe NM, Steeghs N, Tjan-Heijnen VCG, Szallasi Z, Turajlic S, Jamal-Hanjani M, Van Loo P, Bakhoum SF, Schwarz RF, McGranahan N#, Swanton C. . Nature. 2020 Nov;587(7832):126-132. # co-corresponding author
听 - Pennycuick A, Teixeira VH, AbdulJabbar K, Raza SEA, Lund T, Akarca AU,Rosenthal R, Kalinke L, Chandrasekharan DP, Pipinikas CP, Lee-Six H, Hynds RE, Gowers KHC, Henry JY, Millar FR, Hagos YB, Denais C, Falzon M, Moore DA, Antoniou S, Durrenberger PF, Furness AJ, Carroll B, Marceaux C, Asselin-Labat ML, Larson W, Betts C, Coussens LM, Thakrar RM, George J, Swanton C, Thirlwell C, Campbell PJ, Marafioti T, Yuan Y, Quezada SA, McGranahan N, Janes SM. . Cancer Discov. 2020 Oct;10(10):1489-1499. doi: 10.1158/2159-8290.CD-19-1366. Epub 2020 Jul 20. PMID: 32690541.# co-corresponding author
听 - L贸pez S, Lim EL, Horswell S, Haase K, Huebner A, Dietzen M, Mourikis TP, Watkins TBK, Rowan A, Dewhurst SM, Birkbak NJ, Wilson GA, Van Loo P, Jamal-Hanjani M; TRACERx Consortium, Swanton C, McGranahan N. . Nat Genet. 2020 Mar;52(3):283-293. doi: 10.1038/s41588-020-0584-7.Epub 2020 Mar 5. PMID: 32139907.
- Birkbak NJ, McGranahan N. . Cancer Cell. 2020 Jan 13;37(1):8-19. doi:10.1016/j.ccell.2019.12.004. PMID: 31935374.
听 - Rosenthal R, Cadieux EL, Salgado R, Bakir MA, Moore DA, Hiley CT, Lund T, Tani膰 M, Reading JL, Joshi K, Henry JY, Ghorani E, Wilson GA, Birkbak NJ, Jamal-Hanjani M, Veeriah S, Szallasi Z, Loi S, Hellmann MD, Feber A, Chain B,Herrero J, Quezada SA, Demeulemeester J, Van Loo P, Beck S,听McGranahan N#, Swanton C; TRACERx consortium.听. Nature. 2019 Mar;567(7749):479-485 # co-corresponding author
听 - Messaoudene M, Mourikis TP, Michels J, Fu Y, Bonvalet M, Lacroix-Trikki M, Routy B, Fluckiger A, Rusakiewicz S, Roberti MP, Cotteret S, Flament C, Poirier-Colame V, Jacquelot N, Ghiringhelli F, Caignard A, Eggermont AMM, Kroemer G, Marabelle A, Arnedos M, Vicier C, Dogan S, Jaulin F, Sammut SJ, Cope W, Caldas C, Delaloge S,听McGranahan N#, Andr茅 F, Zitvogel L.听. Ann Oncol. 2019 Mar 29. #co-senior author
听 - McGranahan N*, Rosenthal R, Hiley CT, Rowan AJ, Watkins TBK et al,听.Cell. 2017
听 - Jamal-Hanjani, M., Wilson, G. A.,听McGranahan, N.*, Birkbak, N. J., Watkins, T. B. K., Veeriah, S., . . . Swanton, C. (2017).听. 376(22), 2109-2121. 听 *Joint first author
听 - N McGranahan*, A J.S. Furness*, R Rosenthal*, S Ramskov, R Lyngaa (2016),听, Science* Joint first author
听 - McGranahan, N., Favero, F., de Bruin, E. C., Birkbak, N. J., Szallasi, Z., & Swanton, C. (2015).听. Sci Transl Med, 7(283)
听 - de Bruin, E. C.,听McGranahan, N*., Mitter, R., Salm, M., Wedge, D. C., Yates, L., . . . Swanton, C. (2014).听. Science, 346(6206), 251-256*Joint first author
听 - Dewhurst, S. M.,听McGranahan, N*., Burrell, R. A., Rowan, A. J., Gronroos, E., Endesfelder, D., . . . Swanton, C. (2014).听. Cancer Discov, 4(2), 175-185*Joint first author
听 - Murugaesu, N., Wilson, G. A., Birkbak, N. J., Watkins, T.,听McGranahan, N*., Kumar, S., . . . Swanton, C. (2015).听. Cancer Discov, 5(8):821-31 *Joint first author
听 - Favero, F.,听McGranahan, N*., Salm, M., Birkbak, N. J., Sanborn, J. Z., Benz, S. C., . . . Swanton, C. (2015).听. Ann Oncol, 26(5), 880-887*Joint first author
听 - Gerlinger, M., Horswell, S., Larkin, J., Rowan, A. J., Salm, M. P., Varela, I., Fisher, R.,听McGranahan, N., . . . Swanton, C. (2014).听. Nat Genet, 46(3), 225-233
听 - Martinez, P., Birkbak, N. J., Gerlinger, M.,听McGranahan, N., Burrell, R. A., Rowan, A. J., . . . Swanton, C. (2013).听. J Pathol, 230(4), 356-364
听 - Gerlinger, M., Quezada, S. A., Peggs, K. S., Furness, A. J., Fisher, R., Marafioti, T., Vishyesh, H., Shende, H.,听McGranahan, N. . . . Swanton, C. (2013).听. J Pathol, 231(4):424-32
听 - Fisher, R., Horswell, S., Rowan, A., Salm, M. P., de Bruin, E. C., Gulati, S.,听McGranahan, N., . . . Swanton, C. (2014).听. Genome Biology, 15 (8), 433
