Francis Crick Institute scientists have discovered the timing of
key genetic mistakes that fuel tumour growth.
The findings begin to reveal patterns that are common in many
cancer types and provide crucial evidence that, as cancer develops,
the growth of the disease may rely on gene mutations present in
only a small number of cells within the tumour.
This uncovers vital clues explaining why tumours become
resistant to treatment and suggests new strategies for tackling the
problem.
They trawled through publicly available data for over 2,500
tumours from The Cancer Genome Atlas to study the variety of
mutations, and the processes that trigger them, across nine common
cancer types.
Similar to looking at all the living members of a large,
branching clan to work out how they might be related and which
family they belong to, the researchers analysed the relative
proportions of particular genetic faults in the data for each
tumour sample. They compared how common each genetic fault was
across the different tumour types to build up a picture of the
sequence in which they were likely to have emerged during tumour
development.
Certain faults known to be key drivers of cancer growth were
found in all tumour cells, suggesting they happened early on in
cancer development. While other mutations - including those that
can be hit by the new generation of targeted drugs - affected a
smaller proportion of the cancer cells, suggesting they were
occurring later on.
Crucially, the team also discovered that the timing of various
mutations, and the processes in a cancer cell that fuel them, often
followed similar patterns across different tumour types.
For example, they found that later on in tumour development many
cancer cells acquire a hyper-active protein called APOBEC, which
allows cancer cells to sustain a much higher mutation rate than
normal cells. The result is increased genetic diversity in the
tumour, making it more difficult to treat and greatly increasing
the chances of further mutations emerging that allow the disease to
spread and become resistant to treatment.
Understanding which genetic faults are driving the growth and
spread of disease at different time points could help develop new
targeted drugs or drug combinations aimed at genetic changes
present in all rather than just a minority of tumour cells. This
could reveal ways of forcing tumours down an 'evolutionary dead
end' that makes it much less likely resistant cancer cells will be
left behind to carry on growing after treatment.
Professor Charles Swanton of the Crick and the UCL Cancer
Institute, said: "Data from large-scale sequencing studies offer a
snapshot of all the cells in a tumour at a particular moment in
time. We have used a phenomenal public resource provided by the
Cancer Genome Atlas in the USA to drill down further to work out
how cancers change over time and to attempt to identify genetic
events that in turn drive a tumour's growth and ability to
spread.
"This has enabled us to sift out some of the really important
genetic faults occurring in all tumour cells from those that may
play less of a role, or appear in only a few cells. It's only the
tip of the iceberg but I'm optimistic that we'll one day be able to
use evolutionary theory to outsmart many cancers, using carefully
orchestrated combinations of drugs, and therapies that harness the
body's immune system, at key time points."
The paper, Clonal status of actionable driver events and the timing of
mutational processes in cancer evolution, is published
in Science Translational Medicine.