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Inherited mutations in the BRCA1 and BRCA2 genes are associated with strong predisposition to breast and ovarian cancer; lifetime risk is around 85% for mutation carriers. Women at high risk of the disease based on their family history require high levels of surveillance to identify tumours in the early stages; the identification of a familial breast cancer associated mutation makes it possible to test unaffected relatives. Those who test positive for the mutation receive the option of increased levels of surveillance or prophylactic interventions, whilst those who test negative are discharged from surveillance.

However, a new study in the Journal of Medical Genetics suggests that the risk of disease for family members who lack the familial BRCA1/2 mutation may nevertheless remain elevated. The UK researchers examined a total of 277 families with pathogenic BRCA1/2 mutations; 49% of the women (258 in all) tested negative for the family mutation, but 28 of these developed breast cancer and a further four, ovarian cancer. Overall, 6.4% of the family members who did not possess the familial mutation developed breast cancer by the age of 50, compared with just 2% of the general population, leading the researchers to conclude that the relative risk of breast cancer for these family members was raised [Smith, A et al. (2006) J Med Genet Online First, doi:10.1136/jmg.2006.043091].

This apparent discrepancy is proposed to be the result of phenocopies within families – that is, individuals who share the same phenotype (breast cancer) but not the same genetic cause. The risk of breast cancer is known be influenced by additional genes besides BRCA1/2. Another less likely possibility would be the presence of more than one pathogenic BRCA1/2 mutation in the same family. The authors conclude that women from high-risk families who do not carry familial BRCA1/2 mutations should nevertheless be considered at moderate risk of breast cancer, and receive increased levels of surveillance accordingly. Lead author Professor Gareth Evans of the Department of Medical Genetics at St Mary's Hospital in Manchester commented: "We would suggest these women should be considered for annual breast screening between the ages 40 and 49 in the UK…rather than being treated like the general population where compulsory screening begins at 50" (see BBC news report).

Comment: It was already known that other genes besides BRCA1 and BRCA2 must contribute to genetic risk of breast/ovarian cancer; women with a strong family history of the disease are known to be at high risk even if no pathogenic mutation is identified within the family. The findings of this study are an important reminder that multiple genetic factors may be at work even within families where pathogenic or potentially pathogenic BRCA1/2 mutations have been found, and this should inform the management of all family members.