A mutation already linked to several types of cancer doubles the risk of breast cancer in a woman and multiplies men's slight risk even more dramatically, a new study finds.
The protein encoded by the normal version of the gene called CHEK2 or CHK2 signals a cell to stop dividing if its DNA is damaged, says study coauthor Douglas F. Easton, a genetic epidemiologist at Cambridge University in England.
The protein appears to activate the proteins encoded by cancer-fighting genes BRCA1 and p53, says cancer geneticist Daniel A. Haber of the Massachusetts General Hospital Cancer Center in Charlestown, Mass. The full picture of how these genes and their proteins work is far from clear, he says. Nevertheless, he calls the study "fascinating and unexpected." Haber and his colleagues had earlier implicated a CHEK2 mutation in a syndrome that includes breast cancer, brain cancer, and sarcoma, a cancer of connective tissues.
A mutation in BRCA1 imparts more-serious risk than a defective CHEK2 does, Easton says. Studies have shown that a woman with a mutation in BRCA1 faces a 60 percent or higher lifetime risk of getting breast cancer. A woman with a CHEK2 mutation faces a doubling of the standard lifetime breast cancer risk, Easton says, which is roughly 13 percent in the United States.
Only about 1 percent of breast cancers occurs in men. However, having a mutated CHEK2 hikes men's risk 10-fold, the researchers found.
The team detected a CHEK2 mutation in 18 blood samples obtained from 1,620 healthy men and women in Europe and North America. This incidence of 1 in 90 is about nine times as high as that of BRCA1 mutations. Easton and his colleagues report their findings in an upcoming Nature Genetics.
The frequency of the CHEK2 mutation is too low to justify screening in the general population, Easton says. However, for people with other breast cancer risk factors–such as a close relative with the disease–genetic screening and counseling "might be of value," he says.
Douglas F. Easton
Cancer Research UK Genetic Epidemiology Unit
Strangeways Research Laboratory
University of Cambridge
Cambridge CB1 8RN
Daniel A. Haber
Harvard Medical School
Massachusetts General Hospital
Charlestown, MA 02129
Bell, D.W., et al. 1999. Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome. Science 286(Dec. 24):2528-2531. Abstract available at [Go to].
Cui, J., et al. 2001. After BRCA1 and BRCA2–what next? Multifactorial segregation analyses of three-generation, population-based Australian families affected by female breast cancer. American Journal of Human Genetics 68(February):420-431. Abstract.
Khanna, K.K., and S.P. Jackson. 2001. DNA double-strand breaks: Signaling, repair and the cancer connection. Nature Genetics 27(March):247-254.
Lee, S.B., et al. 2001. Destabilization of CHK2 by a missense mutation associated with Li-Fraumeni syndrome. Cancer Research 61(Nov. 15):8062-8067. Abstract available at [Go to].
Matsuoka, S., M. Huang, and S.J. Elledge. 1998. Linkage of ATM to cell cycle regulation by the Chk2 protein kinase. Science 282(Dec. 4):1893-1897. Abstract available at [Go to].
Vahteristo, P., et al. 2001. p53, CHK2, and CHK1 genes in Finnish families with Li-Fraumeni syndrome. Cancer Research 61(Aug. 1):5718-5722. Abstract available at [Go to].