The largest-ever study to sequence the whole genomes of breast
cancers has uncovered five new genes associated with the disease
and 13 new mutational signatures that influence tumour development.
The results also reveal what genetic variations exist in breast
cancers and where they occur in the genome.
Dr Serena Nik-Zainal of the Wellcome Trust Sanger Institute led
analysis of 560 breast cancer genomes; 556 from women and four from
men. This international collaboration included breast cancer
patients from around the world, including the USA, Europe and
Asia.
The results reveal more about the causes of breast tumours and
provide evidence that breast cancer genomes are highly
individual.
Each person's cancer genome is a complete historical account of
the genetic changes that they have acquired throughout life. As a
person develops from a fertilised egg into adulthood, the DNA in
their cells gather genetic changes along the way. This is because
human DNA is constantly being damaged by things in the environment
or simply from wear and tear in the cell. These mutations form
patterns, or mutational signatures, that we can detect and they
give us clues about the causes of cancer.
Dr Nik-Zainal's team hunted for mutations that encourage cancers
to grow and looked for mutational signatures in each patient's
tumour. They found that women who carry the BRCA1 or BRCA2 gene,
and so have increased risk of developing breast and ovarian cancer,
had whole cancer genome profiles that were highly distinctive from
each other and were also very different to other breast cancers.
This discovery could be used to classify patients more accurately
for treatment.
Dr Nik-Zainal said: "In the future, we'd like to be able to
profile individual cancer genomes so that we can identify the
treatment most likely to be successful for a woman or man diagnosed
with breast cancer. It is a step closer to personalised healthcare
for cancer."
Exactly where mutations occur in breast cancer genomes is
important too. Collaborator Dr Ewan Birney, from the European
Bioinformatics Institute, used computational techniques to analyse
the sequence of genetic information held in each of the sample
genomes.
Dr Birney said: "We know genetic changes and their position in
the cancer genome influence how a person responds to a cancer
therapy. For years we have been trying to figure out if parts of
DNA that don't code for anything specific have a role in driving
cancer development. This study both gave us the first large scale
view of the rest of the genome, uncovering some new reasons why
breast cancer arises, and gave us an unexpected way to characterize
the types of mutations that happen in certain breast cancers."
Professor Sir Mike Stratton, Director of the Wellcome Trust
Sanger Institute said: "All cancers are due to mutations that occur
in all of us in the DNA of our cells during the course of our
lifetimes. Finding these mutations is crucial to understanding the
causes of cancer and to developing improved therapies. This huge
study, examining in great detail the many thousands of mutations
present in each of the genomes of 560 cases brings us much closer
to a complete description of the changes in DNA in breast cancer
and thus to a comprehensive understanding of the causes of the
disease and the opportunities for new treatments."
This work was reported in two papers:
Landscape of somatic mutations in 560 breast cancer whole genome
sequences is published in Nature.
The topography of mutational processes in breast cancer genomesis published in Nature Communications.