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Copy Number Variation More Common In Cancer Risk Syndrome

NEW YORK (GenomeWeb News) – Individuals with more copy number variations in their genomes may also be at increased risk for cancer, according to new research.
Researchers from the University of Toronto used high-density oligonucleotide arrays to look at the frequency of CNVs in the general population and in families with Li-Fraumeni, a syndrome predisposing individuals to cancer. The findings, appearing online this week in the Proceedings of the National Academy of Sciences, indicate that CNVs are present at relatively consistent baseline levels. But in individuals with Li-Fraumeni syndrome, CNVs were more prevalent — apparently increasing along with cancer risk.
“Oncologists are in need of better tools to help identify children at a high risk of developing cancer,” senior author David Malkin, co-director of the Cancer Genetics Program at the University of Toronto’s Hospital for Sick Children, said in a statement. “Our use of new high-resolution techniques allowed us to discover that these genetic changes, which we had always thought only existed in tumors, can also be found in the patient’s blood.”
Li-Fraumeni syndrome is caused by mutations in the tumor protein 53 or TP53 gene, a tumor suppressor that maintains genome stability. It is characterized by increased risk for early-onset cancers including breast cancer, cancer of the bones or other connective or supportive tissue, and brain tumors. In general, the syndrome tends to become worse with each generation in affected families. Even so, it’s difficult to predict the type and severity of cancer that individuals with Li-Fraumeni may develop.
In an effort to hone in on the genome-wide changes associated with the syndrome, Malkin and his team characterized the frequency of CNVs in the general population and in those with Li-Fraumeni.
Using Affymetrix GeneChip 250K Nsp microarrays to assess CNVs, the researchers first determined the baseline CNV level in 500 healthy individuals of European descent and in 270 healthy multi-ethnic individuals from the HapMap collection. They also determined each individual’s total structural variation, which takes into account not only the number of CNVs per person, but also the size of these CNVs.
In these populations, the team found a median of three CNVs per person and a median total structural variation of 395 kilobases. Most individuals in this group had four or fewer CNVs in their genome and less than about a megabase of copy variable DNA.
But the number — and size — of CNVs jumped in individuals with Li-Fraumeni syndrome. When they assessed the CNVs in 45 individuals from 11 families with Li-Fraumeni syndrome, eight unrelated individuals with TP53 mutations, and 70 unrelated controls, the researchers discovered that individuals with wild type TP53 had a median of two CNVs per genome while those with mutated TP53 had roughly 12 CNVs per genome. The total structural variation was also much higher in the Li-Fraumeni group.
“Our data demonstrate that the CNV frequency is remarkably similar among healthy individuals, but significantly increased in individuals with germline TP53 mutations,” the authors wrote. “In addition, LFS family members can contain exceptionally large deletions or duplications, as identified by their total structural variation scores.”
And within the group of individuals with TP53 mutations, those who had more CNVs also tended to be those who had already developed cancer. That suggests that these excess duplications and deletions may contribute to the genetic changes associated with cancer.
“We believe that these CNVs can act as the basis for how structural alterations occur in the tumor genome,” lead author Adam Shlien, a graduate student in Malkin’s lab, said in a statement. “In this paper we propose a model for how CNVs contribute to both inherited and sporadic cancers.”
And, given the importance of CNVs in this study, the researchers speculated that testing for such variation may eventually be common in a clinical setting. For instance, they said, doctors may be able to screen TP53 mutation carriers and assign them to cancer risk groups based on their CNV frequency.
“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,” co-senior author Stephen Scherer, director of the Hospital for Sick Children’s Centre for Applied Genomics, said in a statement. “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.”

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