Researchers say they've moved much closer to untangling the genetic threads that raise a woman's chance for breast cancer.
A set of studies published Sunday in the journals Nature and Nature Genetics identified four new breast cancer susceptibility genes, as well as several genetic markers, that are associated with the risk for the disease and that deserve further investigation.
The findings may be the most important genetic discoveries relating to breast cancer genetics since the identification of the BRCA1 and BRCA 2 susceptibility mutations in 1994, experts say.
"With these three reports, we've doubled or more the number of genes in which inherited variations are known to be associated with an increased risk of breast cancer. It's a big quantum of new knowledge," said David Hunter, lead author of one of the papers and co-author on another.
"What we hope will happen is that each of those genes or gene regions will lead us to better understand the mechanisms and biology behind breast cancer," he said. "And that with that better understanding, we'll be able to develop improved means of prevention and treatment."
Hunter is professor of cancer prevention at the Harvard School of Public Health and an epidemiologist with Brigham & Women's Hospital, both in Boston.
Other experts echoed those sentiments. Because the research involved such a large team of international researchers, it was difficult to identify experts who had not been involved with the odyssey in one way or another.
"These findings are really very exciting. Ever since BRCA 1 and BRCA 2, we have been looking for genes associated with breast cancer, and there haven't been many identified," said Heather Spencer Feigelson, a co-author on one of the papers and strategic director of genetic epidemiology at the American Cancer Society in Atlanta. "These are three independent, genome-wide association studies coming out simultaneously that give us some new clues."
"It means a tremendous amount. It's very exciting," added Dr. Stephen Chanock, who was involved in two of the papers and is a senior investigator at the U.S. National Cancer Institute. "This opens a whole series of new doors for therapy and, when we can start to explain it better, prevention."
Mutations in the BRCA1 and BRCA2 genes, the best-known susceptibility genes identified thus far, increase a woman's risk of developing both breast and ovarian cancer. But these genes account for only a small proportion of total breast cancer cases, because the frequency of the mutations is so low in the general population.
"The BRCA1 and 2 genes were milestones in cancer research, but they are rare mutations," Chanock said. "If you have one of those, you have a particularly higher risk of developing breast or ovarian cancer, but 95 percent of the population is not affected by these rare but very significant genes."
Other genes have also been implicated in breast cancer susceptibility but, again, most of these are rare.
"Then the question is, well, maybe it's a conglomeration of things, and what does that complex conglomeration look like?" Chanock continued. "We are just at the dawn of pulling out the major pieces of that."
The first study, appearing in Nature, involved several stages of analysis. That, in turn, led to an analysis of 30 single nucleotide polymorphisms ("SNPs") in 21,860 breast cancer patients and 22,578 controls.
Out of that analysis, the investigators, based in Cambridge, U.K., identified four genes linked with genetic susceptibility to breast cancer (FGFR2, TNRC9, MAP3K1 and LSP1).
The researchers also found five regions of DNA that were present more often in breast cancer patients, suggesting that elements in these regions might raise a woman's risk.
A second study, this one appearing in Nature Genetics, was carried out as part of a collaboration -- called The Cancer Genetic Markers of Susceptibility or CGEMS project -- between Harvard and the NCI. It found that variations of the gene FGFR2 were associated with a heightened risk of breast cancer.
Women of European ancestry who inherited one copy of the FGFR2 mutation increased their breast cancer risk by about 20 percent and by 60 percent if they had two copies.
This same association was found by the Cambridge researchers as well.
These FGFR2 variants, which appear to be involved in cell growth or division, are thought to be present in more than 60 percent of U.S. female adults.
The final paper, also appearing in Nature Genetics, found genetic variants on chromosome 2 and on chromosome 16 that increase the risk of estrogen-receptor-positive breast cancer. One of these variants is located near TNRC9, which was identified in the U.K. study.
Researchers are not advocating that each gene be tested, because the risk from each is relatively small. One day, however, a test for gene combinations may be useful.
"We wouldn't ask to test each of them but, certainly, as we learn more about this, it will give us more clues about the etiology and biology and may lead to differences in treatment," Feigelson said. "This tells us what genes and where to look, and that's the important first step."
"These are all markers. They don't tell you why someone gets breast cancer. They tell us that parts of the genome are very, very important," Chanock added. "We have to figure out what they are."
The technology used in the research only became available last year and is now being applied to a wide variety of diseases, including diabetes and prostate cancer. It will also continue to be applied to the genetics of breast cancer.
"This is sort of the middle of the story," Hunter said. "It is by no means the end of the story."
More information
Visit the U.S. National Cancer Institute for more on its Cancer Genetic Markers of Susceptibility project.
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