Researchers at the Nottingham Breast Unit in the UK have developed an easy and affordable way of screening families for underlying hereditary genetic mutations which predispose them to developing breast cancer, the 3rd European Breast Cancer Conference in Barcelona heard today (Wednesday 20 March).
By testing samples from either two family members affected by breast cancer or from one family member with two tumours, the new test can indicate the presence of mutations in breast cancer genes in 50% of cases, and possibly even more. Once the test has given this indication, doctors can then go on to carry out genetic mutation analysis in only those families where the test has shown a mutation is most likely to be present, and so cut costs by avoiding unnecessary analyses.
José Cid, who carried out the research while he was a clinical research fellow at the Breast Unit, told the conference that an added advantage of this test is that it can be carried out on tumour material stored from previous operations, which enables families to be tested for the presence of a gene mutation when the relative with cancer has already died.
He said: “At present, women who have a high chance of carrying a gene mutation are seen in the family history clinic, where they are offered gene testing only after a full mutational analysis has been done first in the blood of an alive, affected relative. This is time-consuming and expensive. Our alternative procedure requires analysis also in relatives, but this can be done in tissue stored from an operation sometimes carried out many years ago, and it is quick, easy and affordable.”
Mr. Cid recruited 67 families who were expected to be at high risk of developing hereditary breast cancer from the strength of their family history. He did not know in advance whether or not they had mutations in the breast cancer genes BRCA1 and BRCA2.
He analysed samples from two tumours per family (the majority of families with tumours in two relatives, and a few with two tumours in one person) to see whether there was a loss of genetic material close to the BRCA genes and whether the same loss was seen in the same place in both tumour samples. All genes and DNA material come in pairs, and when genetic material from one half of a pair is lost in a cancer cell it is called loss of heterozygosity (LOH). Losses of portions of genetic material occur at random in all cancers (because genetic material is unstable in cancer), and so there is always a “background” level of LOH found in sporadic (i.e. non-hereditary) cancers. The Nottingham team knew that LOH can arise randomly in sporadic breast cancers, but they proposed that if the same LOH was detected in the same place in two different tumours in a family it might point to an underlying hereditary mutation in a breast cancer gene.
Mr. Cid chose five spots or “markers” close to the BRCA1 and BRCA2 genes to search for LOH; this enabled him to maximise the chances of gaining useful information with minimum effort.
He matched the results of the LOH tests with the results from standard genetic mutational analysis. “In 50% (four out of eight) of cases where LOH predicted a mutation in BRCA1 or BRCA2, this was confirmed by mutation analysis,” he said. “In the remaining 50%, mutations may still be present, but the current technique of genetic mutational analysis is not perfect and can not detect all mutations – it usually manages to detect between 50-70% of mutations.
“We also carried out LOH testing in 52 control breast cancer cases – that is, cases of breast cancer in post-menopausal women with no family history present who were therefore very unlikely to have a hereditary gene mutation. In this group we obtained blood from nine people, a lower background LOH level was present and no mutations were found, as one would expect.
“This study has shown that where there is LOH in the same place at two or more markers in two tumours from the same family, then this indicates the presence of a mutated breast cancer predisposition gene.
“This is an easy and affordable procedure which may be useful as a screening tool in at-risk families. More families could benefit from genetic testing because LOH reduces costs by eliminating unnecessary genetic mutational analyses; it also has the potential to halve the cost of mutational analyses because it can indicate whether the BRCA1 or BRCA2 gene is mutated, and therefore only one gene needs to be tested for. In families where mutational analysis is not possible at the moment because they have no alive, affected relative, women can have LOH and risk taking decisions based on the results of LOH alone.
“LOH testing may also find an application in the search for other possible breast cancer genes. As scientists discover genetic regions where there may be potential breast cancer predisposition genes, LOH testing (by using markers near these regions of interest) would help in identifying these genes.”
For further information, contact Emma Mason, Margaret Willson, or Maria Maneiro at the EBCC3 press office in Barcelona, tel: +34-93-364-4487, or Emma Mason's mobile +44-0-7711-296-986, or Margaret Willson's mobile + 44-0-7973-853-347.