Diagnostics & Imaging Week Contributing Writer

LONDON — The family of genes that are known to increase the risk of breast cancer when a woman inherits a faulty version now has another member. A gene called BRIP1 can, in mutant form, double a woman's risk of developing breast cancer during her lifetime.

Nazneen Rahman, professor of Cancer Genetics at the Institute of Cancer Research (Sutton, UK), told Diagnostics & Imaging Week's sister publication BioWorld International: "New breast cancer genes do not come around very often, so this is quite an important finding, even though it is only making a small contribution to the increased risk of breast cancer in breast cancer families."

BRCA1 and BRCA2 account for between 20% and 25% of inherited cases of breast cancer. Women who inherit a mutant copy of one of those genes have a much higher risk of developing breast cancer by the age of 70, at 70%, than women in the general population, whose risk is 10% by age 70.

Since the discovery of BRCA1 and BRCA2 10 years ago, Rahman added, work by her own group and by others had suggested that there were no other genes out there which would confer such a high risk and which would alone account for a substantial proportion of cases of inherited breast cancer.

"Our work leading to the discovery of BRIP1 validates our approach, which is to systematically look at genes that might be related to BRCA1 and BRCA2 in breast cancer families where we know these genes are not to blame," Rahman said. "We know there are many more genes still to find before we have the complete picture of the genetic causes of breast cancer, but with each step we are making progress."

An account of the discovery appears in the Oct. 8, 2006, issue of Nature Genetics in a paper titled "Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles." The study was funded by Cancer Research UK.

Rahman and colleagues, together with collaborators from around the UK, have calculated that mutations in BRIP1 account for about 100 cases of breast cancer diagnosed each year in the UK.

BRCA1 and BRCA2 are both DNA-repair genes. Other genes, identified earlier as conferring an increased risk of breast cancer when mutated, also are known to interact with BRCA1 and BRCA2.

When searching for further breast cancer susceptibility genes, therefore, Rahman's group decided to concentrate on genes encoding proteins that interact with the proteins encoded by the known susceptibility genes. BRIP1 was an obvious candidate for two reasons: First, it encodes an enzyme that interacts with BRCA1, and second, when BRIP1 is inactivated, it wipes out some functions of BRCA1.

Rahman and her colleagues examined DNA from 1,212 women with breast cancer and 2,081 controls. All the individuals with breast cancer had a family history of the disease (or of ovarian cancer), and none of them had mutations in BRCA1 or BRCA2.

When the team sequenced the BRIP1 gene, they found five different mutations — all of them resulting in a truncated protein — in nine of the 1,212 women with breast cancer, compared with two truncating mutations in the 2,081 controls. The researchers calculated the relative risk of breast cancer associated with truncating BRIP1 mutations to be 2.0 (p= 0.012). For women aged under 50 with mutations in this gene, the relative risk of developing breast cancer was 3.5 (p= 0.020).

Sequencing also identified various mutants resulting in missense mutations, but there was no evidence that any of those mutations increased susceptibility to breast cancer.

During the course of the study, other researchers reported that mutations inactivating both copies of the BRIP1 gene are the cause of a type of anemia called Fanconi anemia complementation group J (FA-J). Fanconi anemia is a syndrome of bone marrow failure and leukemia that develops in childhood.

For the biotech industry, Rahman concluded, the challenge now is to develop the technology that would allow the genes currently identified — and those yet to be identified — to be tested for in the clinic. "There is going to have to be a major shift in technology if we are going to be able to assay in a simple, cost-effective and timely fashion, for mutations in lots of genes, in order to give an individual woman advice on her risk of developing breast cancer," she said.