BioWorld International Correspondent

LONDON - A new method of trawling the genome for genes that increase susceptibility to breast cancer has identified five genes that together may account for 4 percent of inherited cases of breast cancer.

Unlike most of the breast cancer susceptibility genes that have been identified to date, which mainly are involved in DNA repair, the new genes appear to have no link to these pathways. Three of them are related to control of cell growth or cell signalling.

Douglas Easton, director of the Cancer Research UK Genetic Epidemiology Unit in Cambridge, UK, told BioWorld International, "Before this study, we had no idea that any of these other genes were important. This finding is important in the long term because it will open up new directions for understanding how breast cancers develop, and for new methods of treatment and prevention."

The study confirms the method as a successful way to identify cancer susceptibility genes.

Easton added, "Now we know these search methods are effective, we think that many more breast cancer genes can be found. These methods are also being applied by Cancer Research UK to find genes for a whole range of other cancers, including prostate, bowel and lung cancer. We expect that a different set of genes will be found for each different type of cancer."

Two of the genetic regions identified contain genes that are thought to increase breast cancer risk by about 20 percent in women who carry one faulty copy of a gene and by between 40 and 60 percent if they carry two faulty copies. For women who inherit two faulty copies, the lifetime risk of developing breast cancer would rise from 1 in 11 to about 1 in 6 or 1 in 7, respectively.

An account of the study appears in the May 27 issue of Nature, titled: "Genome-wide association study identified novel breast cancer susceptibility loci."

Two additional studies, which provide further evidence of genes associated with a higher risk of breast cancer, appear in the May 27 issue of Nature Genetics. One, by David Hunter and colleagues at Harvard Medical School in Boston, identified one of the same genes as has been pinpointed by the Cancer Research UK study as increasing susceptibility to breast cancer.

The other, by Simon Stacey, Kari Stefannsson and colleagues at DeCode Genetics, of Reykjavik, Iceland, reported finding genetic variants on chromosome 2 and chromosome 16, which both increase the risk of oestrogen-receptor-positive breast cancer. One of the variants lies close to one of the genes identified by the Cancer Research UK study.

For the work reported in Nature, Easton and his collaborators studied single nucleotide polymorphisms (SNPs) from throughout the genome. Although there are estimated to be more than 7 million common SNPs in the human genome, because recombination generally takes place at particular "hotspots," many of those are commonly inherited together. Easton's team therefore was able to use a panel of more than 250,000 SNPs to infer information on which groups of SNPs had been inherited by women with breast cancer and by healthy controls.

The first phase of the study, which involved about 400 women with breast cancer and 400 healthy controls, allowed the researchers to identify more than 12,000 SNPs that were inherited more commonly by women with breast cancer.

The scientists then studied the SNPs in almost 4,000 women with invasive breast cancer, and almost 4,000 controls. Finally, the researchers selected 30 of the most common SNPs from the breast cancer patients, and studied them in detail in more than 40,000 patients and controls. That process made it possible to identify several genes that were significantly more likely to be inherited by women with breast cancer than by healthy controls.

Easton said: "These all seem to be genes that are related to growth promotion in some way." One is called FGFR2, which stands for fibroblast growth factor receptor 2. "We already know that this gene is overexpressed in breast cancers, so there is clearly a link between the germ-line mutation and what is going on in the tumor," he said.

Exactly what the other genes do is less clear. One is present on a region of chromosome 8 that already has been identified as playing a role in prostate cancer. Easton added: "This is really very interesting because there are no bona fide annotated genes in that region, yet there is clearly something very important going on there to do with increasing your risk of cancer."

Future studies will examine the biological role of the newly identified breast cancer-risk genes. Easton also expects to identify more such genes by refining the techniques used for the study.