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Closing in on a new gene for breast cancer
By Lone Frank

Genes that predispose women to breast cancer have been intensely hunted for years and now a new player has finally leapt onto the stage. A putative breast cancer susceptibility gene has now been discovered through an international collaboration bringing together 35 scientists from groups in Finland, Sweden, Iceland, Germany, and the United States. Investigating high-risk Nordic families, the team has turned up a finding that may help explain why some women are at increased risk for developing hereditary breast cancer even if they do not carry mutations in the two known breast cancer genes.

‘a gene located in this region normally suppresses cancer development’

The new study published in a recent issue of Proceedings of the National Academy of Sciences builds on analyses of DNA from Swedish, Icelandic and Finnish breast cancer patients from 77 families. "Our extensive cancer registers and genetically relatively homogenous populations make the Nordic countries particularly suitable for such studies," says co-author and molecular biologist Rosa Barkardottir of the University Hospital of Iceland in Reykjavik.

About 10 percent of breast cancer cases are considered heritable and most of them have been attributed to mutations in the BRCA1 or BRCA2 genes, which were isolated in 1994 and 1995 respectively. Women carrying BRCA1/2 mutations have been reported to have as much as an 80-percent risk of developing breast cancer and in some cases ovarian cancer at an early age. According to cancer epidemiologist Jørgen H. Olsen of the Danish Cancer Society, recent investigations in Scandinavian populations suggest that BRCA1/2 mutations account for fewer of the heritable cases than originally anticipated.

"Our strategy was to look for new predisposing genes in patients from families with a strong history of breast cancer where BRCA1/2 mutations are not present," explains molecular biologist Åke Borg of the University Hospital in Lund. The team embarked on a two-step genetic expedition. First 61 Finnish, Swedish and Icelandic breast cancer patients who fit the criteria were recruited and DNA from tumor tissue was compared with control material in so-called comparative genomic hybridization, which reveals deletions in the DNA sequence. Several patients showed loss of a particular region on chromosome 13 indicating that "a gene located in this region normally suppresses cancer development," says Borg.

‘creating new therapies hinges on understanding the biological role of the disease-causing gene’

Next, this finding was supported by genetic studies. An additional group of 334 affected women representing 77 Finnish, Icelandic and Swedish high-risk families with breast cancer that was not attributable to BRCA1/2 mutations donated DNA for linkage analysis. This complex statistical method can determine the likelihood that a gene is inherited and point to the gene's location. "Both linkage analysis and molecular studies of tumor DNA provided evidence for a new breast cancer susceptibility gene in the same chromosomal region," summarizes geneticist Heli Nevanlinna of Helsinki University Central Hospital. But she emphasizes the results are still preliminary.

Many questions still remain. Statistical geneticist Joan Bailey-Wilson of the National Human Genome Research Institute (NHGRI) in Bethesda, Maryland, says confirmation of the linkage in an independent set of families is needed and the collaborators plan to start additional recruiting of Nordic families soon. "We hope other groups will seek to confirm our results in different ethnic groups," adds Nevanlinna.

The spotlighted region on chromosome 13 spans 5 million base pairs, which could represent up to 150 genes. "Pinpointing the actual gene could take months to years, but hopefully the fast emerging data from the mapping of the human genome will speed up the process," predicts Barkardottir. If a gene is isolated researchers will have to determine the disease risk associated with each observed mutation and further down the road lies the most difficult task of determining gene function. "Such work is time-consuming and typically involves a lot of experimental work with animals and cell cultures," says Borg. It took years to determine that BRCA1 and BRCA2 encode proteins that participate in repairing breaks in DNA. "Ultimately, creating new therapies hinges on understanding the biological role of the disease-causing gene," adds Barkardottir.

Though not yet in sight, researchers agree that the first possible clinical application of a new breast cancer susceptibility gene would be a diagnostic test. And cancer geneticist Karen Brøndum of Denmark's Kennedy Institute predicts a strong interest in such a test among women in high-risk families. "The demand for BRCA1/2 testing has doubled in the last year alone and women tell us that they want to know their risk rather than live with uncertainty," she explains. Today, women diagnosed with BRCA1/2 mutations typically choose regular mammography screening as a preventive measure. A very small minority opts for the preventive mastectomy.

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Kainu, T. et al. Somatic deletions in hereditary breast cancers implicate 13q21 as a putative novel breast cancer susceptibility locus. Proc Natl Acad Sci USA 97, 9603-9608 (August 15, 2000).

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