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Cancer evolution, drift and microenvironment selection

  • Full or part time
    Dr C Swanton
  • Application Deadline
    Tuesday, November 12, 2019
  • Funded PhD Project (Students Worldwide)
    Funded PhD Project (Students Worldwide)

About This PhD Project

Project Description

TRACERx is a 10-year longitudinal study of lung cancer evolution from diagnosis to cure or cancer relapse and death implementing DNA and RNA multi-region deep sequencing data with clinical outcome, imaging and immune microenvironmental analysis using imaging mass cytometry in over 700 patients. The study has revealed multiple mechanisms generating cancer cell diversity including APOBEC mutagenesis [1], loss of cancer immune recognition [2, 3], cancer cytotoxics [4], genome doubling events [1] and DNA replication stress [5].

However, inferring selection or neutral evolution from cancer deep sequencing data and how these change over time in a dynamic environment has remained problematic. Moreover, whether selection pressures dictate metastatic potential and its timing remain unclear. Ultimately a more detailed understanding of cancer evolutionary biology may help differentiate “born-to-be-bad” tumours that disseminate widely upon tumour initiation from tumours which progress more indolently or never metastasise. A deeper understanding of these questions will have a fundamental impact on our understanding of disease biology, drug resistance and treatment failure.

Candidate background
The candidate should have a background in one or more of the following: mathematics, statistics , bioinformatics or evolutionary biology. No prior experience in cancer biology is required.

TRACERx represents the most complete dataset in which to address these challenges. This project will work with TRACERx biological, genomics and clinical data in collaboration with the UCL Cancer Institute (McGranahan) to develop state-of-the-art tools to model cancer selection and neutrality and infer the likely tumour micro-environmental influences upon cancer evolutionary dynamics from primary through to metastatic disease across hundreds of patients.

References

1. Jamal-Hanjani, M., Wilson, G. A., McGranahan, N., Birkbak, N. J., Watkins, T. B. K., Veeriah, S., . . . The TRACERx Consortium (2017)

Tracking the evolution of non-small-cell lung cancer.

New England Journal of Medicine 376: 2109-2121. PubMed abstract

2. McGranahan, N., Rosenthal, R., Hiley, C. T., Rowan, A. J., Watkins, T. B. K., Wilson, G. A., . . . TRACERx Consortium (2017)

Allele-specific HLA loss and immune escape in lung cancer evolution.

Cell 171: 1259-1271 e1211. PubMed abstract

3. Rosenthal, R., Cadieux, E. L., Salgado, R., Bakir, M. A., Moore, D. A., Hiley, C. T., . . . The TRACERx Consortium (2019)

Neoantigen-directed immune escape in lung cancer evolution.

Nature 567: 479-485. PubMed abstract

4. McGranahan, N., Furness, A. J. S., Rosenthal, R., Ramskov, S., Lyngaa, R., Saini, S. K., . . . Swanton, C. (2016)

Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade.

Science 351: 1463-1469. PubMed abstract

5. Burrell, R. A., McClelland, S. E., Endesfelder, D., Groth, P., Weller, M.-C., Shaikh, N., . . . Swanton, C. (2013)

Replication stress links structural and numerical cancer chromosomal instability.

Nature 494: 492-496. PubMed abstract

Related Subjects



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