SickKids scientists demonstrate link between DNA copy number changes and cancer risk: Discovery may lead to the early identification of individuals who are predisposed to developing cancer

    TORONTO, Aug. 4 /CNW/ - Scientists at The Hospital for Sick Children
(SickKids) have discovered a link between a newly discovered form of inherited
genetic alteration, termed DNA copy number variation (CNV), and cancer
susceptibility. This work, published online in Proceedings of the National
Academy of Sciences (PNAS), is the first to demonstrate the link between
germline (the genetic material that may be passed from parent to child) CNVs
of DNA and cancer.
    A team of scientists led by Dr. David Malkin, staff physician in the
Division of Hematology/Oncology, and senior scientist at SickKids, and
professor in the Departments of Paediatrics and Medical Biophysics at the
University of Toronto, conducted an extensive analysis of DNA from families
with a rare disease called Li-Fraumeni syndrome (LFS) which causes
susceptibility to cancer. They found that an excess of CNVs was directly
associated with the development of cancer in patients. CNVs, which involve the
duplication or deletion of large segments of DNA, had previously been shown to
occur in cancer cells themselves. This study demonstrates that CNVs also exist
in the blood DNA of LFS patients, and may be passed down from one generation
to the next.
    LFS is a hereditary disease with an increased risk of developing cancer
in childhood and early adulthood. LFS patients carry a mutation in the Tumour
Protein 53 (TP53) gene, which normally functions to maintain the stability of
the genome. As a result of this TP53 mutation, patients are susceptible to
many different kinds of tumours, including breast, brain, blood, bone and soft
tissue cancers. LFS becomes more severe with each passing generation, with the
afflicted offspring usually developing cancers earlier than their parents. The
unpredictability and severity in the types of cancer experienced in LFS have
led to suspicions that other genetic changes are required in addition to
mutated TP53.
    "Oncologists are in need of better tools to help identify children at a
high risk of developing cancer," says Malkin. "Our use of new high-resolution
techniques allowed us to discover that these genetic changes, which we had
always thought only existed in tumours, can also be found in the patient's
blood." The application of this technology is already poised for clinical use
to allow routine patient screening in this type of inherited cancer, and
ultimately other more common forms of cancer.
    Malkin's team collaborated with Dr. Stephen Scherer, senior scientist at
SickKids and director of The Centre for Applied Genomics, to analyze the DNA
from LFS family members and controls, using state-of-the art DNA microarrays -
a method of high-throughput technology used by researchers to quickly scan
through millions of DNA sequences and rapidly interpret large amounts of data.
They found that there is a low baseline number of CNVs that is consistent
across the healthy population. Remarkably, the number of CNVs in LFS patients
was significantly higher. Furthermore there were more CNVs present in LFS
patients who had already developed cancer, suggesting that CNVs accumulate and
may reflect the degree of aggressiveness of the disease. Going forward, the
SickKids team intends to examine the number of CNVs in other childhood and
adult cancer patient populations so that they can better understand how CNVs
contribute to the development of cancer.
    "We believe that these CNVs can act as the basis for how structural
alterations occur in the tumour genome." says Adam Shlien, a graduate student
in Malkin's lab and the study's lead author. "In this paper we propose a model
for how CNVs contribute to both inherited and sporadic cancers."
    According to Scherer, this work has a tremendous impact on families with
cancer predisposition syndromes like LFS. "We anticipate that early screening
will allow us to identify patients with the highest risk so that cancers can
be identified and treated at an earlier stage. Furthermore since the findings
speak to our fundamental understanding of the genetic basis of cancer, this
may lead to advances in personalized medicine for our patient population."
    This research was supported by the National Cancer Institute of Canada
with funds from the Canadian Cancer Society, Genome Canada/Ontario Genomics
Institute, the Canadian Institutes for Health Research, the NARSAD Mental
Health Research Association, the Canada Foundation for Innovation, and
SickKids Foundation.

    The Hospital for Sick Children (SickKids), affiliated with the University
of Toronto, is Canada's most research-intensive hospital and the largest
centre dedicated to improving children's health in the country. As innovators
in child health, SickKids improves the health of children by integrating care,
research and teaching. Our mission is to provide the best in complex and
specialized care by creating scientific and clinical advancements, sharing our
knowledge and expertise and championing the development of an accessible,
comprehensive and sustainable child health system. For more information,
please visit . SickKids is committed to healthier children for
a better world.

For further information:

For further information: Janice Nicholson, The Hospital for Sick
Children, (416) 813-6684,

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