Breast cancer genes examined

Monday September 20 2010

The increased risk of breast cancer caused by a known genetic mutation may be altered by variations in other parts of the DNA, BBC News reported. The website said that the actions of these genetic variants might explain why having a high-risk mutation of a gene called BRCA1 does not always lead to cancer. The presence of some variants raised the risk further and could eventually be used to fine tune screening programmes, the website added.

The news is based on a large international study which furthers our understanding of the genetics of breast cancer and helps explain why some women are at higher risk. It identified two new variants associated with an increased risk of breast cancer for women carrying the BRCA1 mutation, as well as three variants associated with a reduced risk. The idea of fine tuning genetic tests to offer women a more personalised assessment of their risk is certainly appealing. However, before this can be done, we must first understand more about the genetics of breast cancer. It is too early to discuss the use of these findings in preventative treatment.

Where did the story come from?

The study was carried out by researchers from numerous medical and scientific research centres around the world. It was funded by the Breast Cancer Research Foundation and by other organisations who gave grants to individual researchers.

The study was published in the peer-reviewed medical journal Nature Genetics.

The study was described well by BBC News, although the report took a while to explain that the increased risk associated with the newly identified variants was only modest. Researchers are hoping that the results of the study can be combined with data on other (presumably undiscovered) regions of DNA to produce a clearer picture of how these variants affect cancer risk.

What kind of research was this?

This genome-wide association study was set up to identify whether any additional genetic variants were associated with higher risk of breast cancer in women with a mutation of the BRCA1 gene. When functioning properly, the BRCA1 and BRCA2 genes help the body suppress tumours. However, mutations in either of these genes have been linked with an increased risk of breast and ovarian cancer.

What did the research involve?

The researchers analysed the genetic make-up of 1,193 women with BRCA1 mutations who had been diagnosed with invasive breast cancer when they were under 40 years old. The researchers compared their DNA with that of 1,190 women aged over 35 who also had the mutation but had not been diagnosed with breast cancer. They were looking for possible genetic factors that may have influenced why BRCA1 mutations lead to cancer in some individuals but not others. The researchers identified genetic variants that were more common in the group with breast cancer.

There are usually several stages to these types of genetic studies. To confirm their findings from the first stage, the researchers performed a replication study to see whether their initial results were mirrored in a new sample of 2,974 women with the BRCA1 mutation and breast cancer, and 3,012 unaffected women. Further research was then performed on those variants in genes that are known to produce proteins.

In a further step, the researchers analysed an additional 6,800 women with breast cancer who did not necessarily have BRCA1 mutations (called a population-based sample) and 6,613 women without cancer (controls). In a separate study, they analysed a further 2,301 breast cancer cases and 3,949 controls. Again, they wanted to see whether the presence of significant genetic variants from both steps above were associated with particular breast cancer types, including triple negative disease (a type of breast cancer that doesn’t have receptors for oestrogen, progesterone and HER2).

What were the basic results?

In the researchers’ first sample, 96 genetic variants were more common in women with both a BRCA1 mutation and breast cancer than in women with the mutation alone. Five of these variants, all on chromosome 19p13, were significantly associated with an altered risk (both increased and decreased risk) of breast cancer in the replication sample. Of the five variants, two (rs8170 and rs4808611) were associated with an increased risk of breast cancer. The other three were associated with a reduced risk.

Further analysis of one of the variants that increased risk and one that reduced risk in a population-based sample (i.e. women who did not necessarily have BRCA1 mutations) showed that both were strongly associated with a type of cancer called oestrogen receptor-negative breast cancer but not with overall breast cancer risk.

All five variants were also associated with triple-negative disease in a population sample. The researchers discussed the biological mechanisms behind the link between these variants and breast cancer risk.

There was no evidence of a link between any of these five variants and the risk of ovarian cancer, which the researchers also examined.

How did the researchers interpret the results?

The variants were identified in a particular region on chromosome 19. The researchers say that variation at this particular location, “in combination with other risk modifiers”, may turn out to be useful in assessing the risk of disease in women who carry BRCA1 mutations. They say they have shown that they can use genome-wide association studies to further identify gene variants that make women with BRCA1 mutations more susceptible to disease.


This well-conducted genome-wide association study adds to our understanding of the genetic complexities behind the risk of breast cancer. It has identified genetic variants that are more common in women with the BRCA1 mutation who go on to develop the disease. Although the BRCA1 mutation has been linked with an increased risk of disease, not all women who have it will develop breast cancer. Understanding how other risk factors may contribute to disease development is important for researchers, practitioners and ultimately women themselves.

This is valuable research, but it is not yet clear whether it will lead to an improved set of diagnostic or screening tests for high-risk women. Developing risk-scoring tools based on these findings will clearly be a complex task requiring further research and development. Not all of these newly identified variants increased breast cancer risk and there are likely to be others that haven’t yet been found. This study and others like it will add to our knowledge of the genetics of breast cancer, and hopefully one day we will have a clearer idea of why some women have a higher risk of breast cancer than others.

Genetic testing for any disease requires careful weighing up of the benefits and risks for the individual, which can include considerable worry and distress. Any person considering genetic testing to assess their risk of a particular disease should be fully informed and receive counselling to help in making the decision.

Analysis by Bazian
Edited by NHS Choices