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UCL Cancer Institute

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Cancer Genome Evolution Research Group

Group Leader: Dr Nicholas McGranahan

Research

Our lab focuses on using computational methods to explore the cancer genome and anti-tumour immunity within an evolutionary framework. We are based within the CRUK-UCL Lung Cancer Centre of Excellence, located in the UCL Cancer Institute. 

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. 

Allele-Specific HLA Loss and Immune Escape in Lung Cancer Evolution:

A specific genetic alteration that could allow cancer cells to escape the immune system was detected in 40 percent of non–small cell lung cancers (NSCLCs) analysed, according to data presented at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics.

LOHHLA

LOHHLALoss OHeterozygosity in Human Leukocyte Antigen, a computational tool to evaluate HLA loss using next-generation sequencing data: https://bitbucket.org/mcgranahanlab/lohhla


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. 

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.  

We welcome informal enquiries, both from potential collaborators and potential PhD and postdoctoral candidates - please contact Nicholas McGranahan nicholas.mcgranahan.10@ucl.ac.uk


Selected publications

  1. 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
  2. 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
  3. 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
  4. 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)
  5. 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
  6. 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
  7. 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
  8. 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
  9. 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
  10. 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
  11. 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
  12. 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