BioWorld International Correspondent

LONDON - The discovery of another new gene that doubles a woman's risk of breast cancer when inherited in mutant form will help fill in the gaps in our knowledge of how faults in DNA repair cause cancer, researchers predict.

It also brings clinicians closer to the day when they can assess a woman's individual risk of breast cancer, according to whether she has inherited one or more of a spread of mutant genes.

Nazneen Rahman, professor of cancer genetics at the Institute of Cancer Research in Sutton, UK, said: We hope eventually to be able to assess a woman's individual risk, and if it is elevated, we may be able to do something about it. In addition, new treatments are increasingly targeting the DNA repair pathways that these genes operate in, so it may be that women with these types of genetic faults will be suitable for certain types of treatment in the future.'

Women who inherit a mutant form of the newly identified gene, which is called PALB2, have 2.3 times the risk of breast cancer than women of similar ages from the general population. The protein product of PALB2 is known to interact with that of BRCA2, making it the first to do so out of several breast cancer genes identified as conferring a small increased risk of breast cancer.

Other breast cancer genes, such as CHEK2, ATM and BRIP1, which are associated with similar small increases in risk of breast cancer, by contrast, interact with BRCA1.

Together, faults in BRCA1 and BRCA2, which are both DNA-repair genes, are thought to account for 5 to 10 percent of cases of breast cancer.

We know that the PALB2 protein directly interacts with BRCA2. It stabilizes BRCA2 and facilitates its actions. But PALB2 may also have its own role in DNA repair,' Rahman said.

A paper by Rahman and her colleagues describing the role of mutant PALB2 in breast cancer is published in the Dec. 31 issue of Nature Genetics. Its title is PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene.'

The team, funded by Cancer Research in the UK, looked for faults in PALB2 in 923 individuals with a family history of breast cancer, which they knew was not caused by inheritance of mutant BRCA1 or BRCA2. The researchers found mutations in 10 of those individuals, but no mutations in 1,084 controls.

We estimate that faults in the PALB2 gene contribute to around 100 cases of breast cancer in the UK each year,' Rahman said. Interestingly, one of the 10 breast cancer cases we identified as being linked to PALB2 was a male breast cancer, which may mean faults in the PALB2 gene are associated with a higher risk of male breast cancer. We need to investigate this link further before we will know for sure.'

She predicted that some DNA repair genes with a role in breast cancer remain to be found, but that other types of genetic faults, for example those interacting with hormones and other environmental factors, are likely to be identified soon.

In the same issue of Nature Genetics, Rahman's group and a second team of researchers also reported that some people with Fanconi anemia (FA) - a rare type of inherited anemia that leads to bone marrow failure - carry two mutant copies of PALB2.

The paper by Rahman and colleagues is titled Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer.'

The title of the accompanying paper, by David Livingston, of Harvard Medical School, and collaborators, is Fanconi anemia is associated with a defect in the BRCA2 partner PALB2.'

Rahman's group studied 82 children with FA that was not due to any of the 11 genes known to be responsible for the disease. They identified seven children as belonging to a new subtype, which is characterized by aggressive disease, with a high risk of childhood solid tumors including medulloblastoma and Wilms' tumor.

Professor John Toy, medical director of Cancer Research UK, said: All children with Fanconi anemia are already monitored very closely for signs of cancer, particularly leukemia. Identifying children with a unique type of this disease, one characterized by a high risk of developing certain solid tumors, is a significant finding that will assist doctors looking after these particular patients in the future.'