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Rewriting the cancer rulebook

Professor Charles Swanton and colleagues' pioneering studies of the genetic diversity of cancers have provided new insights into the 'rules' governing cancer evolution - with sobering implications for treatment.

The development of cancer is a process, as cells accumulate mutations that promote their proliferation and spread. Although it has long been known that multiple mutations are required to drive cancer, it was generally assumed that these arose sequentially in an orderly succession.

However, work in leukaemia led by Professor Tariq Enver and Professor Mel Greaves, and then by Professor Swanton and colleagues first in renal cancer [1] and then lung cancer [2], revealed that this was too simplistic a view. As cancer cells divide, daughter cells independently acquire new mutations in each generation - undergoing 'branched evolution'. Certain descendants may have a selective advantage, and proliferate particularly well, but an individual tumour will be a mosaic of related but different cells - a phenomenon known as intratumour heterogeneity.

Building on this profound insight, Professor Swanton has sought to understand the general principles or constraints that govern how a cancer evolves, and the implications this has for patient survival.

The evolutionary perspective emphasises the importance of diversity - which provides the raw material on which natural selection can act. Genetic diversity in cancer is created by mutations, including those driven by mutagens such as cigarette smoke or ultraviolet radiation. But cancer genomes can incur huge amounts of damage - not just point mutations but much larger deletions, duplications, rearrangements and even complete duplications of the genome. Chromosomal instability - or mutations that trigger it - is potentially highly dangerous as it can dramatically increase genetic diversity.

Confirmation that this is the case has come from the pioneering TRACERx study, run in collaboration with the CRUK UCL Cancer Trials Centre, in which patients with lung cancer (a relatively simple cancer) and renal cancer (a complex cancer, with both benign and aggressive variants) are being followed from diagnosis through treatment to cure, recurrence or death. Analysis of the first 100 TRACERx lung cancer patients confirmed that chromosome instability was associated with significantly increased risk of recurrence or death [3].

Chromosome instability could therefore be an important marker of poor prognosis. The ability to use this kind of information clinically has been enhanced by the demonstration by the TRACERx team that branching evolution in lung cancer can be detected not just in tumour biopsies but also by analysis of circulating tumour DNA in blood samples [4]. It may therefore be possible to monitor patients after surgery to identify those at risk of recurrence and requiring more intensive follow-up.

The molecular mechanisms that create genetic diversity are a key focus of Professor Swanton's work. He has a particular interest in the APOBEC system, an antiviral defence mechanism. APOBEC enzymes work by modifying nucleic acids and, if their regulation is disrupted, they can start acting on the cell's own DNA - creating a highly damaging 'mutator' phenotype [2].

Another potentially significant mechanism, again emerging from TRACERx studies, is the loss of HLA proteins on the surface of cancer cells, which renders cancer cells invisible to the immune system. HLA proteins play a critical role in immune defences, 'presenting' peptides to T cells, which then destroy the presenting cell. The genetic chaos inside cancer cells typically generates unusual proteins, which are sensed as 'foreign' and presented by HLA proteins to T cells. By eliminating HLA proteins, cancer cells no longer give away their presence to the immune system, giving them more scope to diversify. Indeed, cancers lacking HLA and evading immune detection were found to have undergone more branched evolution [5].

The great genetic heterogeneity of cancers is a major challenge to targeted therapeutics. Among the trillion or so cancer cells in a patient, it is almost inevitable that some exist that are already resistant to a targeted therapy. Darwinian evolution will ensure that those cells will expand once their competitors are eliminated.

But new opportunities are emerging. Diversity may benefit a tumour but it also carries a risk - novel proteins are generated that can be detected by the immune system [6]. By identifying antigens that trigger powerful immune responses, and arose early in evolution so that they are shared by all a patient's cancer cells, it may be possible to engineer and expand T cells that can eradicate a cancer entirely.

  1. Gerlinger M et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med. 2012;366(10):883-892.
  2. de Bruin EC et al. Spatial and temporal diversity in genomic instability processes defines lung cancer evolution. Science. 2014;346(6206):251-6.
  3. Jamal-Hanjani M et al. Tracking the Evolution of Non-Small-Cell Lung Cancer. N Engl J Med. 2017;376(22):2109-2121.
  4. Abbosh C et al. Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution. Nature. 2017;545(7655):446-451.
  5. McGranahan N et al. Allele-Specific HLA Loss and Immune Escape in Lung Cancer Evolution. Cell. 2017;171(6):1259-1271.e11.
  6. McGranahan N et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science. 2016;351(6280):1463-9.

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Professor Charles Swanton