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Women who carry mutations in the BRCA1 and BRCA2 genes have a dramatically increased risk of developing breast cancer: a 36 to 85 percent chance of developing the disease during their lifetime, which is three to five times greater than the average risk rate. Ken Offit, chief of the clinical genetics service at Memorial Sloan-Kettering Cancer Center, in New York, wants to know how the other 15 to 64 percent escape unscathed.

Genetic microarrays that allow scientists to quickly screen the genomes of thousands of patients are finally bringing that question within reach. In a new study, scientists around the globe are collecting DNA samples from women with mutations in BRCA2. Researchers will scour their genomes for variations that are more common in carriers who have made it to old age cancer free. If they’re successful, the study could point to genetic pathways that reveal new ways to treat cancer or prevent it before it even begins.

Because genetic variations that protect against cancer are expected to exert only a moderate effect on breast-cancer risk, scientists need to study thousands of women to find them. And because BRCA mutations are rare, occurring in about 1 in 400 women in the general population (and about 1 in 40 Ashkenazi Jewish women), cancer and genetics centers all over the world are collaborating on the study. Offit talks with Technology Review about the genetics of cancer protection.

Technology Review: Tell us about the new study.

Ken Offit: We’re focusing on two extreme phenotypes in breast cancer. At one end of the spectrum are women who have inherited a predisposing mutation which vastly increases the risk of breast cancer and who develop it at early age. At the other extreme are older women who have not developed cancer, despite having that predisposing mutation. We will search for [genetic variations] that are protective against breast cancer.

It’s a very simple study that we’ve been wanting to do for a long time.

TR: Why is the study only now being carried out?

KO: Two factors have finally come together to make it feasible. The technology is at hand: SNP arrays [microarrays that can quickly detect single nucleotide polymorphisms, or SNPs, across the entire genome]. And through international collaboration, we finally have enough women to do the study.

We already have in hand over 5,000 carriers of BRCA2 from around the world. That’s an extraordinary number of individuals coming from virtually every major cancer and genetics center around the world.

TR: Have genetic factors that are protective against breast cancer been found before?

KO: Candidate gene studies have found some protective markers–for example, a SNP in a gene called rad51, which appears to confer some protection in BRCA2 carriers. It’s a gene involved in the process of DNA damage response and repair.

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Credit: Memorial Sloan-Kettering Cancer Center

Tagged: Biomedicine, genome, genomics, genetic analysis, genome analysis, breast cancer, GWAS

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