A study published in the New England Journal of Medicine
has found that taking a sample from just one part of a tumour may
not give a full picture of its 'genetic landscape'.
Cancer Research UK scientists carried out the first ever
genome-wide analysis of the genetic variation between different
regions of the same tumour using kidney cancer samples. They found
that the majority, around two thirds of gene faults, were not found
in other biopsies from the same tumour.
The findings could help explain why attempts at using
single biopsies to identify biomarkers to which personalised cancer
treatments can be targeted have not been more
successful.
The lead author Professor Charles Swanton, based at
Cancer Research UK's London Research Institute and the UCL Cancer
Institute, said: "We've known for some time that tumours are a
'patchwork' of faults, but this is the first time we've been able
to use cutting-edge genome sequencing technology to map out the
genetic landscape of a tumour in such exquisite
detail.
"This has revealed an extraordinary amount of diversity,
with more differences between biopsies from the same tumour at the
genetic level than there are similarities. The next step will be to
develop drugs that limit this diversity by targeting key driver
mutations that are common throughout all parts of the
tumour."
The researchers - funded by Cancer Research UK, the
Medical Research Council and the Wellcome Trust - compared the
genetic faults in samples taken from different parts of four
separate kidney tumours, and also from sites where the cancer had
spread to other organs.
The samples were donated by patients treated at the Royal
Marsden Hospital under the supervision of Dr James Larkin.
He said: "The idea of personalised medicine is to
tailor treatments to suit individual patients. This study in kidney
cancer has shown significant molecular changes between different
parts of the same tumour. We have also seen differences between
primary kidney tumours and cancer cells that have spread to other
organs. This may be relevant to how we treat kidney cancer with
drugs because the molecular changes that drive the growth of the
cancer once it has spread may be different from those that drive
the growth of the primary tumour."
The researchers identified 118 different mutations - 40 of
which were 'ubiquitous mutations' found in all biopsies, 53 'shared
mutations' that were present in most but not all biopsies and 25
'private mutations' that were only detected in a single
biopsy.
By analysing the location of shared mutations in relation
to the whole tumour, the researchers were able to trace the origins
of particular subtypes of cancer cells back to key driver
mutations. This allowed the scientists to create a 'map' of how the
pattern of faults within the tumour might have evolved over
time.
Professor Swanton added: "For the first time we've been
able to use the pattern of genetic faults in a tumour to trace the
origins of certain populations of cancers cells, much in the same
way as Darwin used his 'tree of life' theory to show how different
species are related.
"This underscores the importance of targeting common
mutations found in the 'trunk' of the tree as opposed to those
found in the 'branches', which may only be present in a relatively
small number of cells. It may also explain why surgery to remove
the primary kidney tumour can improve survival, by decreasing the
likelihood that resistant cells will be present that could go on to
re-grow the tumour after treatment."
Dr Lesley Walker, Cancer Research UK's director of cancer
information, said: "These findings highlight important differences
that exist within tumours and suggest a way to improve the success
rate of personalised cancer medicines. Crucially, they emphasise
the need to build capacity within the NHS for in-depth genetic
analysis of tumours to allow researchers to identify the markers
that best predict who will benefit from targeted
treatments.
"We are now planning to see if these results can be
replicated in larger groups of patients as part of Cancer Research
UK's Genomics Initiative - a set of groundbreaking projects using
the latest high-tech gene sequencing machines to track down the
genetic faults driving different types of cancer."
Original paper: Gerlinger M. et al, Intratumor heterogeneity and
branched evolution revealed by multiregion sequencing (2012),New England Journal of Medicine, DOI:
10.1056/NEJMoa1113205