Cancer Genome Evolution Research Group
Group Leader: Dr Nicholas McGranahan
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’s life history.
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 TCGA (the Cancer Genome Atlas) and ICGC (the International Cancer Genome Consortium) have made thousands of sequenced cancer genomes and exomes publicly available.
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’ overall survival times.
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.
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).
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.
One example of a bioinformatics tool we have recently developed to understand immune escape, is LOHHLA, Loss Of Heterozygosity in Human Leukocyte Antigen.
- Schenk A, López S, Kschischo M, McGranahan N. Germline ancestry influences the evolutionary disease course in lung adenocarcinomas. Evol Appl. 2020 Apr 17;13(7):1550-1557. doi: 10.1111/eva.12964.
- Watkins TBK, Lim EL, Petkovic M, Elizalde S, Birkbak NJ, Wilson GA, Moore DA, Grönroos 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, Dyrskjøt L, Jönsson 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. Pervasive chromosomal instability and karyotype order in tumour evolution. Nature. 2020 Nov;587(7832):126-132. # co-corresponding author
- 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. Immune Surveillance in Clinical Regression of Preinvasive Squamous Cell Lung Cancer. 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
- López 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. Interplay between whole-genome doubling and the accumulation of deleterious alterations in cancer evolution. 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 Genome Evolutionary Trajectories in Metastasis. Cancer Cell. 2020 Jan 13;37(1):8-19. doi:10.1016/j.ccell.2019.12.004. PMID: 31935374.
- Rosenthal R, Cadieux EL, Salgado R, Bakir MA, Moore DA, Hiley CT, Lund T, Tanić 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, McGranahan N#, Swanton C; TRACERx consortium. Neoantigen-directed immune escape in lung cancer evolution. Nature. 2019 Mar;567(7749):479-485 # co-corresponding author
- 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, McGranahan N#, André F, Zitvogel L. T cell Bispecific Antibodies in Node-Positive Breast Cancer: Novel Therapeutic Avenue for MHC class I Loss Variants. Ann Oncol. 2019 Mar 29. #co-senior author
- McGranahan N*, Rosenthal R, Hiley CT, Rowan AJ, Watkins TBK et al, Allele-Specific HLA Loss and Immune Escape in Lung Cancer Evolution.Cell. 2017
- Jamal-Hanjani, M., Wilson, G. A., McGranahan, N.*, Birkbak, N. J., Watkins, T. B. K., Veeriah, S., . . . Swanton, C. (2017). Tracking the Evolution of Non-Small-Cell Lung Cancer. New England Journal of Medicine. 376(22), 2109-2121. *Joint first author
- N McGranahan*, A J.S. Furness*, R Rosenthal*, S Ramskov, R Lyngaa (2016), Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade, Science* Joint first author
- McGranahan, N., Favero, F., de Bruin, E. C., Birkbak, N. J., Szallasi, Z., & Swanton, C. (2015). Clonal status of actionable driver events and the timing of mutational processes in cancer evolution. Sci Transl Med, 7(283)
- de Bruin, E. C., McGranahan, N*., Mitter, R., Salm, M., Wedge, D. C., Yates, L., . . . Swanton, C. (2014). Spatial and temporal diversity in genomic instability processes defines lung cancer evolution. Science, 346(6206), 251-256*Joint first author
- Dewhurst, S. M., McGranahan, N*., Burrell, R. A., Rowan, A. J., Gronroos, E., Endesfelder, D., . . . Swanton, C. (2014). Tolerance of whole-genome doubling propagates chromosomal instability and accelerates cancer genome evolution. Cancer Discov, 4(2), 175-185*Joint first author
- Murugaesu, N., Wilson, G. A., Birkbak, N. J., Watkins, T., McGranahan, N*., Kumar, S., . . . Swanton, C. (2015). Tracking the genomic evolution of esophageal adenocarcinoma through neoadjuvant chemotherapy. Cancer Discov, 5(8):821-31 *Joint first author
- Favero, F., McGranahan, N*., Salm, M., Birkbak, N. J., Sanborn, J. Z., Benz, S. C., . . . Swanton, C. (2015). Glioblastoma adaptation traced through decline of an IDH1 clonal driver and macro-evolution of a double-minute chromosome. Ann Oncol, 26(5), 880-887*Joint first author
- Gerlinger, M., Horswell, S., Larkin, J., Rowan, A. J., Salm, M. P., Varela, I., Fisher, R., McGranahan, N., . . . Swanton, C. (2014). Genomic architecture and evolution of clear cell renal cell carcinomas defined by multiregion sequencing. Nat Genet, 46(3), 225-233
- Martinez, P., Birkbak, N. J., Gerlinger, M., McGranahan, N., Burrell, R. A., Rowan, A. J., . . . Swanton, C. (2013). Parallel evolution of tumour subclones mimics diversity between tumours. J Pathol, 230(4), 356-364
- Gerlinger, M., Quezada, S. A., Peggs, K. S., Furness, A. J., Fisher, R., Marafioti, T., Vishyesh, H., Shende, H., McGranahan, N. . . . Swanton, C. (2013). Ultra-deep T-cell receptor sequencing reveals the complexity and intratumour heterogeneity of T-cell clones in renal cell carcinomas. J Pathol, 231(4):424-32
- Fisher, R., Horswell, S., Rowan, A., Salm, M. P., de Bruin, E. C., Gulati, S., McGranahan, N., . . . Swanton, C. (2014). Development of synchronous VHL syndrome tumors reveals contingencies and constraints to tumor evolution. Genome Biology, 15 (8), 433