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Scientists discover three new genetic variants linked to male breast cancer

Breast cancer cell

Image: Breast cancer cell. Credit: Anne Weston, Francis Crick Institute.

UK scientists have discovered three new genetic changes that increase the risk of breast cancer in men, in the world’s largest genetic study of the causes of male breast cancer to date.

Researchers, largely funded by Breast Cancer Now, identified three common variations in DNA that predispose men to developing breast cancer, bringing the total known number to five.

All three genetic variants are known to be linked to female breast cancer but scientists at The Institute of Cancer Research, London, and Queen’s University Belfast found the changes to have a greater effect on breast cancer risk in men than in women.

The study involved 1,380 men with breast cancer, primarily from the Breast Cancer Now Male Breast Cancer Study based at The Institute of Cancer Research (ICR). The team found that three genetic changes, called rs9371545, rs554219 and rs78540526, increased the risk of developing breast cancer in men by approximately 47, 45 and 61 per cent respectively.

The researchers then analysed over 170 SNPs known to affect risk in women, finding significant overlap in the genetic risk factors for the disease in men. The results suggest male and female breast cancer may have a very similar genetic basis ― a discovery which could in future lead to new preventive treatments for men and women.

The study also found that men at the highest genetic risk were almost four times more likely to develop breast cancer than those at lowest risk.

‘Major step forward’

Breast Cancer Now described the discovery as a “major step forward in our understanding of male breast cancer”, calling for greater awareness of the disease in men and for research into the shared genetic causes of male breast cancer and the most common form in women (ER+), to develop risk-reducing drugs and other interventions to prevent more cases among those at increased risk.

The study was funded by Breast Cancer Now and Queen’s University Belfast, and is published in the Journal of the National Cancer Institute.

While breast cancer in men is very rare, around 370 men are diagnosed with the disease every year in the UK, and around 80 men lose their lives each year.

There are a number of different treatments for breast cancer in men depending on the features of the tumour, including surgery, hormone therapy, radiotherapy, chemotherapy and targeted drugs – all of which were first developed to treat the disease in women.

More than 95 per cent of all breast cancers in men are oestrogen receptor (ER) positive ― compared to up to 80 per cent of cases in women ― meaning that they contain proteins called oestrogen receptors and can be stimulated to grow by the hormone.

Shared genetic causes in men and women

Men with a strong family history of breast cancer among female relatives are known to be at greater risk, and around 10 per cent of male cases are caused by mutations in the BRCA2 gene. But the exact causes of the disease in men are not yet understood, and, for years, there has been considerable debate about whether male and female breast cancer are distinct from one another.

While mutations in genes such as BRCA2 can increase the risk of breast cancer by a great deal, these faults are relatively rare – and major research has shown that single-letter changes to our DNA code (called Single Nucleotide Polymorphisms or SNPs) also influence cancer risk.

With up to 15 million places where SNPs can exist across our genome, these changes are relatively common.

In a major new genetic analysis pooling data from multiple studies worldwide, researchers led by Dr Nick Orr at the Breast Cancer Now Research Centre at The Institute of Cancer Research (ICR) and at Queen’s University Belfast compared the genomes of 1,380 men with breast cancer to 3,620 men without.

The scientists discovered three new SNPs that were significantly associated with an increased risk of breast cancer in men: one on chromosome 6 (rs9371545) and two on chromosome 11 (rs554219 and rs78540526).

The researchers then investigated the extent of the shared genetic causes of the disease in men and women by evaluating 172 regions in the genome linked to female breast cancer, for an association with male breast cancer.

The team found a strong correlation between the genetic risk factors of male and female breast cancer, with 20 per cent of SNPs that influence (increase or decrease) the risk of breast cancer in women also having an effect on male breast cancer risk.

The study also observed some important differences, with some SNPs carrying a greater increase in risk for women than for men or vice versa, and some SNPs also changing the risk in opposite directions for men than for women.

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More precise risk testing

Having identified this overlap, the researchers then investigated how well a DNA test (313 SNP risk score), which was designed to estimate breast cancer risk in women, worked for men.

They found there was nearly a four-fold increase in risk between men in the highest genetic risk category and those in the lowest (OR= 3.86), and that the distribution of cases across risk categories was similar to that observed in women.

The findings add to the major discovery in 2012 from the Breast Cancer Now Male Breast Cancer Study by the same authors, that a single change in the genetic code of a gene called RAD51B can increase the risk of breast cancer in men by up to 50 per cent.

It is hoped that the discovery of new locations in the genome linked to male breast cancer could now enable scientists to identify the biological mechanisms that cause the disease to develop in men, and could ultimately lead to the development of new preventive drugs for those at high risk.

While further research would be needed, the authors also suggest the findings could in future help to develop more precise risk testing for men carrying BRCA2 mutations, enabling them to understand whether they are at additional or lower risk due to other genetic changes, which could help guide decisions around any risk-reducing steps.

More alike than different

Lead author Dr Nick Orr, who led the research at the ICR, and the Patrick G. Johnston Centre for Cancer Research at Queen’s University Belfast, said:

“There has been much debate about whether breast cancers in women and men are distinct from one another. Our study has shown, for the first time, that the genetic factors influencing susceptibility to male breast cancer and the most common type of female breast cancer are much more alike than they are different.

“Our findings suggest that the underlying biology that affects how breast cancer develops and grows are probably similar in men and women. This means that advances in prevention and treatment for the disease may be of benefit to all patients, irrespective of their gender.”

Dr Simon Vincent, Director of Research, Services and Influencing at Breast Cancer Now, which funded the study, said:

“This study, which shows more of a similarity between the genetic causes of the disease in men and women than previously thought, is a major step forward. Our knowledge of breast cancer in men is limited, because male breast cancer is rare which makes it difficult to collect enough tissue or blood samples to research and understand the disease. Research like this is critical to improving our understanding of the disease in men and we hope the Breast Cancer Now Male Breast Cancer Study will continue advancing our knowledge.

“We now look forward to further research into the shared genetic causes of male breast cancer which could lead to developing risk reducing treatments and interventions to help prevent more cases among those at increased risk in the future.

The Breast Cancer Now Male Breast Cancer Study is the largest collection of DNA and tumour samples from men with breast cancer in the world, with over 1,000 men who have been diagnosed participating, as well as over 1,000 men without breast cancer. Based at the ICR, the study was established in 2008 to pinpoint the genetic, environmental and lifestyle causes of breast cancer in men.


Nicholas Orr breast cancer genetics male breast cancer
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