Genes That Fend Off Cancer

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.

KO: Sometimes taking drugs like tamoxifen [a drug that interferes with the activity of estrogen and is used to treat breast cancer] can reduce risk in BRCA carriers. But it has risks.

TR: Could the same approach find protective factors for other types of cancer?

KO: In theory, the same approach could be applied to other hereditary cancer syndromes, such as colon cancer, thyroid cancer, or pediatric cancers. The question is whether the same factors that protect women from getting breast cancer or other cancers in the face of strong genetic predisposition will be generalizable to the population at large. We also hope to look at that.

TR: Will the results of the study be useful for genetic screening?

KO: The risk for breast cancer [in BRCA carriers] over the course of a lifetime can range from 30 to 40 percent up to 80 to 90 percent, based on different studies. The hope would be that by mapping modifiers [genetic variants that either increase or decrease risk], we would be able to tell women which end they are closer to.

Women who have mutations that modify risk may well be interested in tailoring their preventive medical management to an adjustment in risk. Someone carrying a series of modifiers that indicate they are at particular risk at early age might elect to have more frequent surveillance or surgical risk reduction.

TR: Will this study lead to new drugs that protect against the development of cancer?

KO: In any gene discovery experiment, the long-term goal is to better understand the biology of the process, which can then serve as the rationale for pharmacologic development. Certainly, the identification of genes that are protective against all the processes in aging, including the increasing cancer risk, would be interesting targets for drug development.