Scientists discover link between DNA copy number changes and cancer risk

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.