Study uncovers limitations of US breast cancer genetic testing

Commercial genetic testing offered to women with a family history of breast cancer may provide false reassurance in some cases, a new US study shows. Researchers based at the University of Washington in Seattle studied women affected by hereditary breast cancer, who had all received negative results following BRCA1 and BRCA2 genetic testing. However, 12 per cent of these women had unusual BRCA gene mutations that commercial tests are not designed to detect. In a further six per cent of patients, the team identified mutations in other genes known to increase the risk of breast cancer. The scientists, who published their findings in the Journal of the American Medical Association (JAMA), suggest that more effective tests should be developed for such women.

Most cases of breast cancer are not inherited, but around 5-10 per cent are due to a gene mutation - often, but not always, in one of two 'BRCA' genes. Whilst most women have a 13 per cent chance of developing the disease in their lifetime, those with BRCA1 or BRCA2 mutations can face up to an 80-85 per cent chance. They also have an increased risk of ovarian cancer. In the past few years, researchers have identified other genes which, when mutated, can increase the risk of breast cancer. For example, in 2004, an international team confirmed that having a CHEK gene mutation doubles a woman's lifetime risk of the illness to 25 per cent. In the latest study, the scientists looked for mutations in the BRCA1, BRCA2 and CHEK genes, as well as the TP53 and PTEN genes - also linked to breast cancer.

The team studied 300 women with a family history of breast cancer who had developed the disease. They found that 35 of these women had received 'false negative' BRCA gene test results because they had unusual mutations, such as large chunks of the gene missing or rearranged. While the commercial test can detect small-scale BRCA gene mutations, it misses larger mutations, since these can only be detected using different methods - such as a technique called 'multiplex ligation-dependent probe amplification (MLPA). A further 14 patients (five per cent) had CHEK gene mutations, while three (one per cent) had inherited mutations in the TP53 gene. None of the women had a PTEN gene mutation.

Women with a high genetic risk of breast cancer can be offered increased screening, or sometimes preventative surgery to cut their chances of developing the disease. However, the JAMA study highlights the limitations of the tests currently used to identify such women in the US. The authors write that 'the clinical dilemma is what to offer to women with a high probability of carrying a mutation in BRCA1 or BRCA2 but with negative commercial test results'. The Utah-based company Myriad Genetics holds an exclusive BRCA gene testing licence in the US, unlike in Europe, where alternative testing kits capable of detecting unusual BRCA gene mutations are available.

Study leader Mary-Claire King told New Scientist magazine that the development of new tests is being stifled by inappropriate patent rules in the US, saying ' we need a competitive marketplace'. In reply, Bill Hockett of Myriad said that the company plans to introduce a more comprehensive BRCA genetic test kit later in 2006, which will use an approach similar to MLPA.