Charles Swanton

 

Deciphering cancer evolution and immune evasion in four dimensions

Intratumour heterogeneity is increasingly seen as a major impediment to cancer therapy and achieving cures in metastatic disease. Genome instability fosters cell-to-cell variation, providing the substrate upon which selection can act. Our laboratory and others have shown that the APOBEC family, genome doubling events, structural and numerical chromosomal instabilities and mutagenic cytotoxics are some of the genome instability mechanisms through which cancers acquire further fitness. However, the absence of a large longitudinal cohort of multiple tumour samples collected over space and time from diagnosis through to death with extensive clinical data has limited insight into the the rate at which new variance occurs in cancer genomes and its impact upon selection and immune evasion. The TRACERx/PEACE clinical studies focus on the evolution of non-small cell lung cancer genomes over space and time. This study provides spatially separated and longitudinally collected tumour samples from diagnosis through to death, subject to DNA sequencing at unprecedented scale and depth that will enable cancer genome instabilities and their impact upon selection and the evasion of cancer immune surveillance to be deciphered. The successful applicant will have interests and experience in one or more of these key areas: cancer bioinformatics, immunity or cancer genome instability.

1. de Bruin, E. C. et al (2014)
Spatial and temporal diversity in genomic instability processes defines lung cancer evolution.
Science 346: 251-256. PubMed abstract

2. McGranahan, N. et al (2016)
Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade.
Science 351: 1463-1469. PubMed abstract

3. Dewhurst, S. M. et al (2014)
Tolerance of whole-genome doubling propagates chromosomal instability and accelerates cancer genome evolution.
Cancer Discovery 4: 175-185. PubMed abstract

4. Abbosh, C. et al (2017)
Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution.
Nature 545: 446-451. PubMed abstract

5. Jamal-Hanjani, M. et al (2017)
Tracking the evolution of non-small-cell lung cancer.
New England Journal of Medicine 376: 2109-2121. PubMed abstract