Mutant Gene Linked to Increased Risk of Breast Cancer
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Close relatives of women with a faulty version of the CHEK2 gene as well as bilateral breast cancer are at increased risk for breast tumors of their own, British researchers have reported.
First-degree female relatives of women with bilateral breast cancer and a normal CHEK2 gene are already at high cumulative risk of breast cancer - 23.8% by age 80 compared with an expected cumulative risk of 7.9% for the population as a whole, according to Nicola Johnson, D.Phil., of the Institute of Cancer Research here.
But when the faulty gene, dubbed CHEK2*1100delC, is also present, the rate more than doubles to 58.8%, Dr. Johnson and colleagues reported in the Oct. 28 issue of The Lancet.
CHEK2 codes for a kinase involved in repairing the DNA of the breast cancer susceptibility gene BRCA1 and the oncogene p53. The CHEK2*1100delC mutant doesn’t produce a useful kinase, earlier studies have shown.
Based on those and other studies, the researchers say, CHEK2*1100delC is a “plausible candidate” for a gene that confers a low cancer risk by itself, but in combination with other genes may create a wider spectrum of risk.
In this study, 469 women with bilateral breast cancer were genotyped for the variant CHEK2 gene and seven had it. Then the researchers calculated the prevalence of cancer in first-degree relatives of the 469 women.
They found:
- 139 of the women had at least one relative with breast cancer, and 33 had a relative with prostate cancer.
- Male first-degree relatives also had a high rate of breast cancer; five cases were seen, where only 0.34 would have been expected.
- Among the seven women with the variant gene, six had a relative with breast cancer and two had one with prostate cancer. The breast cancer risk for relatives of carriers was significantly higher than for relatives of non-carriers, at a confidence level of p=0.001.
The researchers didn’t screen for mutant BRCA1 and BRCA2, noting that the frequency of the variant CHEK2 gene in breast cancer patients with mutated BRCA1 or BRCA2 is the same as in controls.
The reason for that, they suggested, is that once either BRCA1 or BRCA2 is mutated, losing the function of CHEK2 doesn’t make matters worse.
The clinical utility of the finding may lie in risk assessment, said co-author Olivia Fletcher, Ph.D., of the London School of Hygiene and Tropical Medicine. About 2,000 cases of bilateral breast cancer are seen every year in Britain, she said, and about 2% of those women carry the faulty version of the gene.
Testing for the gene in women with a family history of breast cancer—and especially those with a first-degree relative with bilateral disease—“could be clinically useful for predicting personal risks,” Dr. Fletcher said.
On the other hand, there’s little immediate clinical impact, said Debbie Saslow, Ph.D., director of breast and gynecological cancer for the American Cancer Society. “There’s nothing that a doctor is going to do differently for the next breast cancer patient who walks in,” she said.
The genetic basis for breast cancer, she said, is usually not a single dominant mutation in a gene such as BRCA1. Instead, it is thought to be a combination of genetic factors, each with a small impact, whose total eventually leads to cancer.
The apparent large impact of the variant CHEK2 gene reported in this study, Dr. Saslow said, is difficult to accept. “I don’t know how much you can tell from seven people,” she said.
But the line of research—trying to find genes whose activity in combination with others leads to cancer—is “very interesting,” she said. “We need this kind of research,” Dr. Saslow added.
Source: The Lancet
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