Inheriting the wrong version of a gene called CHEK2 doubles a woman's risk of developing breast cancer, Cancer Research UK scientists confirm in a major new international study published in the June edition of the American Journal of Human Genetics.
CHEK2 is the first 'low risk' gene to have been definitely established as a risk factor. It follows the identification in the mid-nineties of the high-risk genes, BRCA1 and BRCA2.
The possibility of offering genetic testing for this gene in women with a strong family history of breast cancer is now being researched.
The link between CHEK2 and breast cancer was first proposed in 2002, when a faulty version of the gene was found to be present in some cases with a strong family history of breast cancer. 'Strong family history' indicates at least two close family members have had the disease.
Today's research, coordinated and analysed by Cancer Research UK's Genetic Epidemiology Unit at the University of Cambridge, examined the genes of breast cancer patients and the wider population in the UK, Australia, Finland, Germany and the Netherlands.
The report confirms that the faulty version of the gene, called CHEK2*1100delC, was more common in women diagnosed with breast cancer than in healthy women. In total, they examined the CHEK2 genes of 10,860 women with breast cancer and 9,065 healthy women.
The 1100delC variant was found in 201 women with breast cancer (1.9%) and in 64 healthy individuals (0.7%). Scientists calculate from this that having the variant CHEK2 gene approximately doubles the risk of developing breast cancer, whether or not there is a history of breast cancer in the family.
Lead researcher Professor Doug Easton, of the Cancer Research UK Genetic Epidemiology Unit, says: "Women with a strong family history of breast cancer can already receive genetic tests for the BRCA genes. The next step will be to evaluate whether testing for CHEK2 is useful in the clinic. At the moment it is not clear in what contexts CHEK2 testing would be appropriate.
"As we identify more genes that impact on hereditary breast cancer, we move closer to a comprehensive genetic test to accurately assess the risk of inheriting the disease."
Women in the general population in the UK have a one in nine chance of developing breast cancer at some point in their lifetime. Carrying CHEK2*1100delC would increase this risk to about one in four. CHEK2 is the first confirmed 'low risk' gene. Scientists believe a number more exist, each pushing up the risk of breast cancer to a moderate degree.
The data suggest the increase in risk was greater for women diagnosed at a younger age. Hereditary factors are generally more important in cancers that occur in younger women.
Professor Easton adds: "This is perhaps the largest study of its kind. It is the most reliable method for calculating the impact of potential breast cancer genes, and is also being applied to other types of cancer."
Scientists believe the normal CHEK2 gene shuts down cells in a safe and controlled way upon detection of DNA damage. This prevents the cell from passing on faulty DNA, and allows time for repair mechanisms to be engaged. If a normal cell is like a car on the motorway, CHEK2 is responsible for spotting problems, pulling onto the hard shoulder and calling the AA.
CHEK2*1100delC is missing a vital piece – the brake pedal in the car – and is unable to initiate shutdown. Carrying this version means faults in other genes are more likely to evade the body's own repair processes and replicate themselves, potentially leading to a tumour.
Professor Robert Souhami, Director of Clinical and External Affairs at Cancer Research UK, says: "Identifying the first of a new set of breast cancer genes puts us in a much better position to tackle breast cancer, both through testing high-risk groups and eventually through new clinical strategies. "
Notes for editors CHEK2*1100delC is only found in about 2% of all breast cancer patients, which is why general testing would be impractical. For women with a strong family history of breast cancer, however, screening for the variant would help in assessing each woman's individual risk.
Women with mutations in the BRCA1 and BRCA2 genes have a 50-80% chance of developing breast cancer. CHEK2 does not affect this risk because it is part of the same mechanism in cells, but it is thought to be the first of a group of low-risk genes that may explain hereditary breast cancer in families with normal copies of BRCA1 and 2.
This study did not look at breast cancer in men. About 1% of breast cancers are diagnosed in men. Earlier studies did identify CHEK2 as a risk factor in male breast cancer, and further analyses are ongoing.
Information on breast cancer and genes at: http://www.cancerhelp.org.uk.
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