Key Words
Breast cancer, genetic mutation, CHEK2 gene. (Definitions of many terms related to cancer can be found in the Cancer.gov Dictionary.)
Summary
Women who carry an abnormal variant of a gene known as CHEK2 are three times more likely to develop breast cancer than women who do not have the genetic mutation, a large study by Danish researchers has found. Along with BRCA1 and BRCA2, the CHEK2 gene is now confirmed as a risk factor for breast cancer.
Source
Journal of Clinical Oncology, published online July 31, 2006 (see the journal abstract).
(J Clin Oncol. 2006 Jul 31; [Epub ahead of print])
Background
Some women who have a strong family history of breast cancer have inherited genetic abnormalities, or mutations, that increase their risk for the disease. The so-called BRCA1 and BRCA2 mutations are the most common genetic abnormalities known to be linked to a high risk for breast cancer. However, BRCA1 and BRCA2 mutations account for fewer than one in 10 breast cancer cases. Families in which no one carries a BRCA1 or BRCA2 mutation may still have a strong history of breast cancer. This suggests that other genetic risks for breast cancer have yet to be identified.
In 2002, researchers showed that a mutation in a gene known as CHEK2 increased risk for breast cancer in women from families with a strong history of the disease. CHEK2 normally produces a protein that helps to prevent tumor cells from growing uncontrollably. The mutated form of the CHEK2 gene fails to do its job.
The authors of the 2002 study estimated that women who carried the CHEK2 mutation were at double the risk for breast cancer. Subsequent studies suggested that the CHEK2 mutation might increase risk for prostate and colorectal cancer, as well. However, many of these studies were small and most were retrospective - that is, researchers’ conclusions were based on looking back at what happened to patients in the past. This type of study is generally considered less reliable than a prospective study, in which researchers follow patients forward in time to see what happens to them.
The Study
Researchers in Denmark wanted to confirm whether and to what extent the CHEK2 mutation increased risk for breast, colorectal, and prostate cancer in the general population. They studied 9,231 people who had been monitored for cancer development for an average of 34 years.
The study participants had been interviewed and examined periodically since 1976. Their records contained information about their medical histories, families’ disease history, and smoking and alcohol habits. For women, the number of pregnancies and births had been recorded. Participants’ DNA was analyzed using blood samples they had given between 1991 and 1994. Researchers found out which participants had been diagnosed with cancer by consulting the Danish Cancer Registry, which records 98 percent of all cancers in Denmark.
In addition, the researchers studied 1,101 women with breast cancer who were recruited at a local hospital. The participants gave blood and completed questionnaires that asked about their medical history, family history of breast cancer, pregnancies and births, use of birth control pills or hormone replacement therapy, and alcohol consumption. These women were compared with 4,665 women who were in the same age range but were cancer-free.
Genetic tests were performed on blood samples from all study participants to identify the presence of the CHEK2 mutation. To reduce the chance of incorrect results due to variation in the way the genetic tests were done, all the tests were conducted in the same lab using identical procedures. The researchers then used statistical techniques to estimate cancer risk in both those who had the mutation and those who did not.
The study’s senior author is Borge G. Nordestgaard, M.D., of Herlev University Hospital in Herlev, Denmark.
Results
Half of 1 percent (0.5 percent) of the study participants were found to have the CHEK2 mutation. Women who carried the mutation were 3.2 times more likely to develop breast cancer than those who did not. However, the researchers found no statistically significant increase in risk for colorectal cancer, prostate cancer, or cancer in general among either male or female mutation carriers.
Limitations
Because almost all of the participants in this study were white and of Danish descent, the findings do not shed light on how common the CHEK2 mutation is in people of other races and ethnicities or on whether the mutation confers a similar risk of cancer in other races and ethnic groups.
Comments
This study’s results “confirm beyond a doubt” that women who carry the CHEK2 mutation have a two- to threefold elevation in the lifetime risk for breast cancer, says Jeffery P. Struewing, M.D., of the National Cancer Institute’s Laboratory of Population Genetics.
The current study is the first prospective study of the cancer risk associated with the CHEK2 mutation, says Struewing. Its findings and those of earlier studies of the association between the CHEK2 mutation and breast cancer have shown “astonishing consistency,” he adds.
Studies to date, which have been conducted in predominantly white populations, show that the CHEK2 mutation occurs in roughly one in every 200 people, Struewing says. This makes it about twice as common as the BRCA1 and BRCA2 mutations, but still relatively uncommon.
On average, a woman with a CHEK2 mutation has about a 20 percent to 30 percent lifetime risk of getting breast cancer, according to Struewing. By contrast, the lifetime risk for a woman with a BRCA1 or BRCA2 mutation averages about 60 percent.
Women from families with a strong history of breast cancer may wish to talk to their doctor or to a genetic counselor about the pros and cons of being tested for breast-cancer susceptibility genes, says Struewing. They may also want to talk to their doctor about steps they can consider taking that may reduce their risk of the disease.
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