University of Nottingham. UK: A new study involving researchers at The
University of Nottingham has revealed how children with an aggressive
cancer predisposition syndrome experience a never before seen flood of
mutations in their disease in just six months.
The syndrome, called ‘biallelic mismatch
repair deficiency’ (bMMRD) causes multiple brain tumours, lymphomas and
gastrointestinal cancers by the age of 10. As a result these children
rarely survive into adulthood.
While most cancers grow progressively,
developing genetic mutations over many years, researchers at The
Hospital for Sick Kids in Toronto, Canada, the Wellcome Trust Sanger
Institute and the Children’s Brain Tumour Research Centre in Nottingham,
were shocked to find that children with this syndrome develop more
mutations than any human cancers by far — as many as 20,000 mutations in
as little as six months.
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The new paper, published online in Nature
Genetics, suggests a previously undiscovered mechanism for cancer
progression which could lead to more targeted treatment for these
patients and indeed for more common cancers.
‘Great flood’
Children
with biallelic mismatch repair deficiency, or bMMRD, have mutations in
the genes responsible for mismatch repair and therefore cannot fix
mistakes in DNA while the cell is dividing (or replicating). This study
identifies a secondary mutation which occurs only in tumour cells in an
enzyme called polymerase, which is a second safeguard that helps to
effectively repair mutations while the DNA replicates. The combination
of these two mutations leaves patients with no ability to repair
mistakes that may occur while DNA is replicating, and causes a rapid
wave of cancer that the investigators have dubbed the “great flood.”
Professor Richard Grundy from the
University’s Children’s Brain Tumour Research Centre said: “This study
provides a major step forwards in understanding why certain children are
more susceptible to developing multiple cancers and can screen for this
eventuality. In turn, this study allows us to begin to understand the
steps that lead to cancer developing. Ultimately, we hope this leads to
treatments to avoid the presently inevitable consequences of this
predisposition syndrome”
Implications for diagnosis and treatment
Dr Uri
Tabori, co-principal investigator of the study from Genetics &
Genome Biology at SickKids, Toronto said: “In other cancer
predisposition syndromes like BRCA1 and Li Fraumeni syndrome,
we know that there is a genetic mutation that predisposes the
individual to cancer, but we do not know the secondary mutation, or
genetic driver that actually causes the cancer to occur. Our findings
indicate the genetic driver that causes this ‘great flood’ of cancer
mutations in patients with bMMRD. The secondary mutation in the enzyme
polymerase causes a unique signature of mutations that is present in 100
per cent of the cases. This has important implications for both
diagnosis and targeted treatment of this devastating disease.”
International consortium for cancer genetics
The
Children’s Brain Tumour Research Centre in Nottingham is part of an
international consortium run by SickKids, Toronto, that offers free
genetic testing, genetic counseling and surveillance of cancers in
children and family members with bMMRD. Using genetic and clinical
information and tumour samples gathered from each patient, the research
team was able to take a deeper look at this cancer predisposition
syndrome and for the first time they are able to tell the story of how
this cancer develops.
“We were able to describe how many
mutations develop, how fast they occur, how many mutations the tumour
can sustain, and the type of mutation that occurs, which we found is
unique to bMMRD cancers,” says Dr Adam Shlien, lead author of the study
and Associate Director of Translational Genetics and Scientist in
Genetics & Genome Biology at SickKids.
“Additionally, by studying a rare cancer
syndrome we were able to have an unobstructed view on how cancer
develops and learn not only about how we can help these patients, but
also about cancer progression in general.”
Because the high number of mutations is so
specific to bMMRD syndrome, researchers are now able to detect children
who are carriers just by sequencing the tumour.
“If the child has a very high number of
mutations then we know immediately that they have this cancer
predisposition syndrome,” said Dr Shlien.
Towards tumour cell death
The
team may have also found a clue that may help to develop a novel
treatment that promotes tumour cell death. The observation that tumour
cells reach a threshold of 20,000 mutations and cannot overcome it
suggests that the tumour cannot withstand any more, and more mutations
may cause cell death. Future research may explore how certain
pharmacological agents may push these cancer cells over the mutational
edge and cause the tumour cells to die.
It’s hoped findings from this study will
also lead to more effective treatments for more common cancers such as
colon, gynaecological cancers and recurrent malignant gliomas (cancer in
the brain or spine) since they share the same mutations in the mismatch
repair genes as bMMRD patients).
The study was supported by BRAINchild
Canada, the Canadian Institutes of Health Research (CIHR), Wellcome
Trust Sanger Institute and SickKids Foundation.