New Clues to Hereditary Breast Cancer
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By Regina Nuzzo

New Clues to Hereditary Breast Cancer

A genome-wide search has turned up new breast cancer genes

By Regina Nuzzo


In the past, scientists searching for genes connected to complex diseases had to hunt down one gene at a time. Most often they came up empty-handed. But new technologies can cast a wider net and search the entire genome at once. This summer, three large studies brought in some of the methods’ first payoffs: four genes and three genetic regions that increase breast cancer risk.

Unlike variations in the well-known genes BRCA1 and BRCA2, which are rare but linked to high breast cancer risk, the alterations at the new sites may increase a woman’s chances of cancer only slightly. Yet genes like these can add up, says genetic epidemiologist Douglas Easton, the director of the Cancer Research UK Genetic Epidemiology Unit in Cambridge, England. With the new findings, researchers can now account for 25 percent to 30 percent of hereditary breast cancers.

Even more genes for breast cancer are likely to be found in the next few years using whole-genome approaches, says epidemiologist David Hunter at the Harvard School of Public Health. Such discoveries could help uncover new biological pathways for the treatment of the disease.

The new methods—known as genome-wide association studies—can examine up to half a million regions of DNA simultaneously from the thousands of participants required for these studies. Researchers first do a wide scan of genes in a small number of women to identify potential targets—followed by more focused scans in larger groups of women. Using these techniques, a consortium of researchers led by Easton examined genetic information from nearly 50,000 women from four continents, about half of whom had breast cancer.

The results, published in the June 28 Nature, identified five important sites on the women’s chromosomes: the genes FGFR2, TNRC9, MAP3K1 and LSP1, plus an unnamed region on the eighth chromosome. Certain inherited variations at these sites were more common in women with breast cancer than in those without it.

The gene with the biggest impact was FGFR2. Inheriting two altered copies of this gene can raise a woman’s chance of developing breast cancer in her lifetime by about two-thirds, the researchers found. (By comparison, one altered copy of BRCA1 or BRCA2 raises a woman’s risk between three fold and seven fold.)

Two other genome-wide association studies, both published in the July 1 Nature Genetics, provided further evidence of the link between certain genetic variations and breast cancer. One study led by Hunter examined DNA from 6,000 women and found FGFR2 to be associated with sporadic postmenopausal breast cancer, which arises without a history of breast cancer in the immediate family. An investigation of genes from more than 22,000 women by deCODE Genetics, a biopharmaceutical company headquartered in Reykjavík, Iceland, found two other genetic regions, on the second and 16th chromosomes, where variations increase the risk of breast cancer that responds to estrogen—also known as estrogen receptor–positive breast cancer.

More investigation of the results is needed, but eventually, tests for these and other genetic sites should be able to more precisely predict a woman’s breast cancer risk, says Kari Stefansson, the president and co-founder of deCODE Genetics.

One criticism of genome-wide association studies is the potential for them to falsely pick out unimportant genes. But researchers in these studies used statistical tools to minimize those problems, says epidemiologist Thomas Sellers, the director of the Moffitt Research Institute in Tampa, Fla.

A strength of the whole-genome approach lies in its naiveté, Sellers adds. “With this new technology, we can pretend we know nothing,” about cancer gene location, he says. “It allows us to uncover genes we never would have suspected would be involved in cancer.”