Breast cancer: new genetic clues

Monday May 10 2010

“Five newly discovered genetic variants” raise the risk of breast cancer, reported The Guardian. It said new research has found that women with the variants are 16% more likely to develop the disease.

This genetic analysis study compared the DNA of more than 16,500 women with breast cancer and a family history of the disease with about 12,000 unaffected women. One in nine women will be affected by breast cancer at some point in their lives, and having a first degree relative with the disease can increase risk.

In addition to finding the five new variants, 13 associations identified in previous research were also confirmed. The researchers say that having all five of the new variants explains about 1.2% of the familial risk of breast cancer, while other known variants together account for about 28% of the risk. Combined, these associations account for only 30% of the risk and more research will need to uncover the other genes that contribute to the remaining risk.

It is important to emphasise that having these variants does not mean that someone will definitely develop the disease, only that the variants are linked with an increased risk.

Where did the story come from?

The study was carried out by researchers from the Institute of Cancer Research in Surrey, and various medical and academic institutions in the UK and the Netherlands. The study was funded by the Wellcome Trust and by Cancer Research UK. The study was published in Nature Genetics, the peer-reviewed scientific and medical journal. This analysis article appraises the uncorrected proof version of this research paper.

News coverage has provided a clear account of this research, although it should be emphasised that this study investigated which genetic factors are common in women who have inherited breast cancer, i.e. this study specifically researched women with a family history of the disease. One in 20 breast cancer cases are thought to be inherited, and several genetic variants responsible for this have already been identified. This study has identified five more.

What kind of research was this?

The study was a genome-wide association study that investigated the association between genetic variants and breast cancer. It included only women who had both breast cancer and a family history of the disease. Genome-wide association studies, a form of case-control study, provide a way to examine the association between genetic factors and disease.

The researchers explain that recent studies have identified 13 variants that are associated with an increased risk of breast cancer. However, they say that these appear to play only a small role in the approximately doubled risk of breast cancer seen in first-degree relatives of affected women. Their study was an attempt to identify additional variants.

What did the research involve?

The researcher recruited 3,659 UK breast cancer cases, all with a family history of the disease. The women’s genetic codes were analysed and compared with those from 4,897 control women who did not have breast cancer. To make control subjects comparable to cases, they are usually matched in terms of characteristics such as age, although it is unclear from this publication whether matching was undertaken in this study.

As is common in this type of research, a second group of cases and controls was recruited to validate the associations seen in the first phase. This included 12,576 cases and 12,223 controls. In this second phase, the researchers specifically assessed the contribution of the 15 variants that they found to be linked with breast cancer in their first analysis. The variants studied did not include those that were already known through prior research. In this second part of the study, the cases were women with breast cancer but not necessarily a family history of the disease.

What were the basic results?

In the first phases, the study found a significant association between breast cancer and seven different genetic variants, all of which had been linked with the disease in previous research. Therefore this finding confirmed known associations, particularly that two variants on chromosome 10 (rs2981579 and rs3803662) were most strongly linked with breast cancer.

In the second phase of their study, the researchers identified five new variants (on chromosomes 9, 10 and 11) that were associated with disease. They say that these newly identified variants account for approximately 1.2% of the family risk of breast cancer.

How did the researchers interpret the results?

The researchers say that they have identified five new variants that are associated with breast cancer risk in women with a family history of disease. They say that it is likely that further additional variants may be identified if their data is followed up.


This well-conducted genome-wide association study adds to what is known about the familial risk of breast cancer. The researchers note that the previously identified 13 variants and their five new ones together account for 8% of the familial risk of breast cancer. They also know that mutations in BRCA1 and BRCA2 genes and other regions account for about another 20% of familial risk. The rest, they say, is likely to be due to a combination of a large number of common variants that have smaller individual effects.

It is important to interpret these complex findings about risk in their context: most women do not get breast cancer and several factors beyond family history, such as age and post-menopausal obesity, can contribute to the risk. The majority of breast cancer cases occur in women with no family history of disease.

The genetics of breast cancer are clearly complex, and further studies are needed to determine what other genetic factors further contribute to risk. This study showed links with variants (changes of a single letter in the genetic code) rather than whole genes (such as  BRCA1 and BRCA2). This means that more study is needed to identify how each variant affects breast cancer risk. Women who were heterozygous for the variants (i.e. had one variant at each variant position as opposed to two) had between 5% and 16% (maximum) increased risk of having breast cancer compared to those who did not have the variant. The combination of having all five variants was not assessed in this study. The combination of having all five variants was not assessed in this study.

Findings about which genes increase the risk of breast cancer may play a future role in contributing to screening tests, which are currently based on identifying whole genes. Women who are identified by this system as having a genetically-increased risk of the disease are currently offered different management to the general population, with more intensive screening offered to women who carry faulty TP53, BRCA1 and BRCA2 genes.

Analysis by Bazian
Edited by NHS Choices