In a long-delayed harvest from the human genome project, researchers say they have found six new sites of variation in the genome that increase the risk of breast cancer.
Together with already-known genes, the discovery means that a sizable fraction of the overall genetic risk of breast cancer may now have been accounted for, researchers say, and much of the rest could be captured in a few years.
The findings do not point to any new treatment and are too little understood to serve as the basis of a diagnostic test. But they are a critical step toward understanding the biology of breast cancer, scientists say, from which new treatments should emerge.
Understanding the genetic basis of common disease was the promised payoff of the $3 billion human genome project, which was completed in 2003 but has taken some time to show many tangible results. The logjam seems to be breaking. Last month, seven new DNA variations associated with diabetes were discovered, and advances with other diseases are expected to be announced soon.
The new findings have been made possible by new instruments, known as chips, which enable up to 500,000 points of variation on the human genome to be tested simultaneously for possible association with disease. But to attain statistical strength, large numbers of patients must be recruited, which has prompted otherwise competitive groups to work together.
Using the new chips, scientists can compare breast cancer patients with healthy individuals, looking for variant sites on the DNA of the human genome which seem associated with the disease. Because the chips sample each patient’s entire genome, the new approach is known as a whole genome association study.
With this approach, a large consortium of breast cancer scientists, led by Douglas F. Easton of the Cancer Research-UK Genetic Epidemiology Unit in Cambridge, England, says it has found five new sites on the genome where a common variation confers a risk of breast cancer. Their findings were reported Sunday in the journal Nature.
Two of the same sites of variation have been found by a second team, led by David Hunter of the Harvard School of Public Health. Decode Genetics, a gene-finding company based in Iceland, has also identified two new sites of variation, one of which is the same as one found in Dr. Easton’s study. The reports from Dr. Hunter and Decode Genetics were published online in the journal Nature Genetics.
Scientists involved in the three studies expressed confidence that most of the genetic risk of breast cancer will be detected through the whole genome association approach. “Once the dust has settled, yes, it’s possible we may have captured most of the genetic variation,” Dr. Easton said.
Genes already known to be associated with breast cancer, such as BRCA1 and BRCA2, carry a high risk but are rare in the general population. The new DNA variations are quite common but confer a lesser risk.
A team lead by Simon N. Stacey of Decode Genetics reports that 25 percent of women of European descent carry one copy of a DNA variant on the second of the 23 human chromosomes, conferring a 44 percent greater risk of breast cancer than for women without it, and that 7 percent of women have inherited two copies, with a 64 percent greater risk.
The sites of variation discovered by Decode and the other two groups do not lie in genes and for the most part have no known biological function, though some are conjectured to control the activity of nearby genes. It is purely on the basis of statistics that the sites of variation on the DNA are believed to be associated with disease.
Their discoverers say that the sites will, when understood, reveal new biology that underlies the progression toward breast cancer. But not everyone is convinced.
Mary-Claire King, a biologist at the University of Washington in Seattle who pioneered the search for the BRCA1 cancer gene, criticized the statistical basis of the studies and suggested they should not have been published until the biological significance of the suspect sites had been established.
“I believe the motivation to publish based on so little biological or genetic evidence,” she said, “is that an enormous amount of money has been put into these efforts and hence the need to see positive results is huge.” Her principal criticism of the three studies’ statistics is that when 500,000 sites of variation are tested all at once for association with disease, many may come out positive just by chance, not because of any real link.
Dr. Easton, Dr. Hunter and Kari Stefansson, Decode’s chief executive, all said the criticism was correct in principle but could be sidestepped, as they had each done, by taking the few most promising sites in one whole genome association scan and testing them in a second population.
Dr. Stefansson rejected the suggestion that the three groups should not have published their statistical findings until the biology of the sites was worked out, saying that science proceeds in small steps and that “we never have the entire story on day one.” With publication, the sites are available for other scientists to investigate.
All three scientists expressed confidence that their whole genome association studies have avoided the many pitfalls of the past and are pointing to sites of variation that either cause disease or lie close to those that do so.
“This is the apotheosis of the genome project and the HapMap, to be able to look diagnostically at the whole genome,” Dr. Hunter said, referring to a map of variation in the human genome. “Suddenly all at once we have half a dozen robust associations.”
Dr. Stefansson said firmly, “The statistics are not leading us astray.”
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