TORONTO - Canadian researchers have uncovered a genetic anomaly in people with a higher-than-normal risk of developing cancer that could lead to a blood test for detecting their tumours early, when the disease is most treatable.
The discovery, which involved families with the rare inherited disorder Li-Fraumeni syndrome, could also have implications for understanding how various types of cancer arise in the broader population, the scientists say.
In a study led by Dr. David Malkin of Toronto's Hospital for Sick Children, researchers determined that individuals affected by LFS have greater variation in their DNA compared to those without the condition.
They found that people with LFS have an increase in what are known as copy number variations, or CNVs - the duplication or deletion of large segments of DNA. The study found that CNVs also exist in the blood DNA of LFS patients and may be passed from one generation to another.
Li-Fraumeni syndrome increases the probability of developing specific cancers in childhood and early adulthood, among them soft tissue and bone cancers, brain tumours and breast cancer. There are about 2,000 families worldwide known to have the disorder, but Malkin said doctors believe the number is actually larger.
Most people with LFS have a mutation in their P53 gene, which normally provides stability to the DNA.
The study, published online Monday by the Proceedings of the National Academy of Sciences, showed that subjects with a P53 mutation in blood cells had a significantly higher frequency of CNVs than control subjects without the genetic alteration.
"So it would imply that people who have a mutation in this gene and are susceptible to cancer have inherently regions of their DNA which are duplicated or deleted and therefore are unstable," said Malkin, a pediatric oncologist at Sick Kids. "And that may have something to do with the mechanism by which they develop cancer."
Furthermore, family members who carry the mutated gene -- but had not yet experienced a malignancy -- were found to have fewer CNVs than their relatives who had already developed cancer.
"So something's changing," Malkin said, but added that it's not known whether the gene itself is altered or whether unstable regions of the DNA change over the years so that they acquire more duplications or deletions.
"What is also striking is that with each successive generation, the cancers tend to occur earlier in age and may also be more aggressive biologically," said Malkin, noting that many people with LFS must feel like ticking time bombs.
Luana Locke of Maple, Ont., northwest of Toronto, is among those with LFS. Her mother died of breast cancer at 35 when she was six, following the death of her mother's twin sister from the same malignancy. Her own sister died of a brain tumour at age nine and earlier this year, her brother's son succumbed to soft-tissue cancer on his fifth birthday.
Locke, 36, has not escaped her family's genetic propensity for cancer, although she is the only one to have survived. At 25, she was diagnosed with breast cancer while pregnant with her first child and subsequently had both breasts removed. Both her 11-year-old son and her daughter, almost two, also carry the mutated gene.
While she worries about the emotional toll that LFS may take on her kids when they're old enough to understand it fully, Locke refuses to give in to the ticking-time-bomb mentality.
As it stands, she and her children have blood tests and abdominal ultrasounds every three months, as well as separate MRI scans of the brain and body every six to 12 months to detect any cancers that might have developed.
Malkin said the aim now is to develop a test that would predict in what organ and at what age a cancer is likely to develop, based on similar CNV patterns in relatives and members of other LFS families.
"So rather than what we have to do now -- look for everything at every age, which becomes an extreme burden on the patients and their families -- you may be able to say for such and such a person in the family, we only need to focus on this tumour type, starting from this age," he said.
Locke said such a screening tool would be "a gift" to families like hers that could give "hope for the future, hope that in an LFS family that the legacy of loss will end."
Malkin suggested the CNV finding could have implications beyond Li-Fraumeni and apply to at least some cancers that develop in those without the inherited syndrome.
"We know cancer to be basically a disease of genetic instability in the cancer cells and all we've done here is use an unusual model to show that that instability is actually present in every cell in every person," he said.
Heather Chappell, senior manager of cancer control policy for the Canadian Cancer Society, said studying small populations like those with LFS makes it easier to find genetic differences that may increase the risk of cancer, so scientists know what to look for in the population at large.
"This is exciting because it's one more piece of the genetic puzzle of why some people may develop cancer and others not," she said of the Sick Kids' study. "And we can take the (findings) from this small group and see if it applies to the general population, and it may help explain some of those sporadic cancers we haven't been able to before."
