Cancer risk genes: could PALB2 be BRCA3?

A new study suggests that mutations in a gene called PALB2 are just behind BRCA1 and BRCA2 mutations as a leading genetic risk factor for breast cancer.

The findings, published in the New England Journal of Medicine, indicate that women with mutations in the PALB2 gene have, on average, a one in three chance of developing breast cancer by the age of 70.

PALB2 is known to interact with both BRCA1 and BRCA2, with all three genes playing an important role in repairing damaged DNA. PALB2 was first linked with breast cancer in 2007 (see BioNews 390) but the associated risk of developing the disease had not yet been established.

Dr Marc Tischkowitz from the University of Cambridge, who led the study, said: 'Since the BRCA1 and BRCA2 mutations were discovered in the mid-90s, no other genes of similar importance have been found and the consensus in the scientific community is that if more existed we would have found them by now. PALB2 is a potential candidate to be "BRCA3"'.

The PALB2 Interest Group, an international team of researchers, analysed data from 154 families without BRCA1 or BRCA2 mutations, which included 362 people with PALB2 gene mutations. The scientists found that for people carrying a PALB2 mutation the risk of developing breast cancer was 35 percent, but could be even greater if there was also a strong family history of breast cancer.

Additionally, the researchers found that women with PALB2 mutations who were born more recently tended to be at a higher lifetime risk of developing breast cancer than those born earlier.

A similar phenomenon has been observed in BRCA mutation carriers and the reasons for it are unclear. The scientists speculate that factors such as later age at first childbirth, smaller families and earlier cancer diagnosis may play a part.

Reassuringly, only a very small proportion of women worldwide carry PALB2 mutations. Study co-author Professor William Foulkes, from McGill University in Montreal, Canada, told CBS News that roughly one in a thousand women are thought to be carriers. Further studies are required to obtain a more precise figure.

All the same, the researchers at Addenbrooke's Hospital, part of Cambridge University NHS Hospitals Trust, have developed a test for PALB2 mutations, which will become part of their clinical service.

Dr Tischkowitz said: 'Now that we have identified this gene, we are in a position to provide genetic counselling and advice. If a woman is found to carry this mutation, we would recommend additional surveillance, such as MRI breast screening'.

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