- Cancer is caused by a
series of genetic changes or 'driver' mutations that convert normal cells to
- These driver mutations in turn might be triggered by
'passenger' mutations thought to be incidental occurrences.
- Targeting passenger mutations could pave
the way for a novel therapeutic approach to treat breast
Mutations that occur in critical areas of
the breast cancer genome referred to as 'hotspots
' lead to a
cascade of genetic alterations or damage, which ultimately cause the
development of breast cancer, according to a study conducted at the Wellcome
Trust Sanger Institute.
of the Study
team conducting the study specifically looked at numerous 'passenger' mutations
that occur in cancer cells to determine if they were indeed benign and
incidental findings in cancer cells or whether they played an active part in breast
‘Targeting specific ‘tandem duplications’ that influence breast cancer development could open up newer therapeutic options for breast cancer.’
of the Study
The study team assessed 560 breast cancer
genomes from all parts of the world including USA, Europe and Asia. They looked
for areas where specific genetic changes or mutations referred to as tandem duplications
A tandem duplication is said to happen
when a small segment of the DNA is copied and attached into a neighboring part of the
DNA creating multiple copies of that DNA segment in the genome.
Findings of the Study
- It was found that there were at least 33 locations in the breast cancer genome where these tandem
duplications occurred frequently, in many different women.
- Surprisingly, many of these tandem duplications were found to occur in critical areas of the
breast cancer genome. These included genes that are already known to be
associated with breast cancer and in areas of the genome that 'turn on'
multiple genes. These regulatory areas are termed 'super enhancers'. Damage to the regulatory areas would naturally
cause uncontrolled activation of several genes.
Prof Gerard Evan from the University of
Cambridge, said, "Remarkably, we also found that these
acquired hotspots for tandem duplications coincide with genome regions where we
find not only inherited genetic changes that increase the risk of developing
breast cancer, but also controllers of genes that specify the identity of
breast epithelial tissue. This is a first report that demonstrates a link between
the acquired and the inherited genetic changes that drive breast cancers."
These findings led the scientists to
believe that these tandem duplications might not be actually benign in nature
but might actually trigger further genetic changes, thus initiating a cascade
culminating in breast cancer development.
The driver mutations also vary in their
capacity to cause cancer development; some of the mutations might be weak and
others may be stronger. However, the overall cumulative effect of these
changes might cause the cancer to be more aggressive.
According to Dominik Glodzik, first
author on the paper from the Wellcome Trust Sanger Institute, "DNA in
breast cancers is heavily restructured by many tandem duplications. We were
curious whether this mutational signature influences how cancer develops. From
our research, it now looks like some of these tandem duplications are not just
unimportant passenger mutations, but actually create new driver mutations for
Duplications in Other Cancers
The authors of the study also assessed
other cancers such as ovarian and pancreatic cancers to determine the
occurrence and nature of tandem duplications.
Not surprisingly, they found tandem
duplications in these cancers too but in different
areas of the genome than breast cancer
. This is explained by the fact that
different genes are activated in various tissues. More research is needed to
get further information and knowledge on ovarian and pancreatic cancers
In the words of Dr Serena Nik Zainal,
lead author from the Sanger Institute, "This research has shown a new
genetic mechanism for generating drivers in cancer, which we have found not
only in breast cancers, but also other cancers. It is really important to
identify and study tumors with this mutational signature of tandem duplications,
because if it can create many new drivers, then it has potentially devastating
consequences making tumors more aggressive.
"This is a mutational signature that
should be a target for therapeutic intervention. Further study is needed to understand this mechanism, and for finding out whether tumors with tandem duplications at these
hotspots could respond to certain treatments better than others."
- Dominik Glodzik, Sandro Morganella, Helen Davies,
Peter T Simpson, Yilong Li, Xueqing
Zou, Javier Diez-Perez, Johan
Staaf, Ludmil B Alexandrov, Marcel Smid,
Arie B Brinkman, Inga Hansine Rye, Hege Russnes, Keiran Raine, Colin A Purdie, Sunil R Lakhani, Alastair M
Thompson, Ewan Birney, Hendrik
G Stunnenberg, Marc J van de
Vijver, John W M Martens,
Anne-Lise Børresen-Dale, Andrea L Richardson, Gu Kong, Alain Viari. A
somatic-mutational process recurrently duplicates germline susceptibility loci
and tissue-specific super-enhancers in breast cancers. Nature Genetics