BioWorld International Correspondent

LONDON - The discovery that women who inherit a mutant copy of the BRCA1 gene are at increased risk of developing a whole range of cancers in addition to cancer of the breast and ovary highlights the need for new screening techniques for cancer, researchers say.

The Breast Cancer Linkage Consortium (BCLC) reports that women with a defective BRCA1 gene also have an increased risk of cancer of the uterus, cervix, fallopian tubes, peritoneum, pancreas and colon.

Douglas Easton, director of the Cancer Research UK Genetic Epidemiology Unit at the Strangeways Research Laboratory of the University of Cambridge, told BioWorld International, "These findings could have implications for the management of women who have a family history of breast or ovarian cancer and undergo screening to detect mutations in BRCA1. The issue is whether those identified as having mutations should have other forms of screening or treatment."

At present, Easton said, a woman who is a carrier of mutant BRCA1 would either have prophylactic surgery or mammography plus ultrasound. However, if the increased risk of uterine cancer in such women were firmly established, then clinicians would want to be able to offer some specific and noninvasive screening for that as well, he said. It is not available at the moment.

On behalf of the BCLC, Easton, together with colleague Deborah Thompson of the same institution, published a paper describing the study in the Sept. 19, 2002, issue of the Journal of the National Cancer Institute. The paper is titled "Cancer Incidence in BRCA1 Mutation Carriers."

The BCLC gathered data on about 12,000 men and women from 700 families with a history of breast or ovarian cancer living in Europe and North America. Using statistical techniques, they calculated the cancer risk among people with a mutated BRCA1 gene compared with the general population.

For men who carried the defective gene, the overall risk of developing cancer (apart from breast cancer) was very close to that which would be expected in the general population. For female carriers, the situation was different: Their risk of developing cancer at sites other than the breast or ovary was "markedly elevated."

Those women had more than double the usual population risk of developing cancers of the colon, the pancreas, the uterine body, the cervix, other cancers and cancers of unknown site. The most frequent sites for "other cancers" in women included the peritoneum, the abdomen, the intestinal tract and female genital organs.

The study also showed that the relative risk of developing cancer of the fallopian tubes was nearly 50. The researchers say that increased relative risk is comparable to that for ovarian cancer, and equates to an absolute risk of 1.6 percent by the age of 80.

"It is important to realize that not every woman with an altered BRCA1 gene will develop breast or ovarian cancer and the same applies to the other cancers linked to the mutation in this study," Easton said. "Though there is a big increase in the relative risk to women with the faulty gene, the absolute risk for these other cancers is still quite low. For example, women with the mutation were twice as likely to develop pancreatic cancer than women with a normal BRCA1 gene but the absolute risk for the cancer in women with the faulty gene is as low as 1 percent."

The BCLC already has published a similar study looking at increased risk of cancer among people with a mutation in a related gene, BRCA2. This study found that BRCA2 mutations are associated with increased risks of male breast cancer, prostate cancer and pancreatic cancer, and with possible increased risks for gallbladder cancer, stomach cancer and melanoma.

Easton told BioWorld International that the excess of prostate cancer and pancreatic cancer in people carrying the BRCA1 mutation was much smaller than that in people carrying the BRCA2 mutation, while the excess of abdominal cancers in women carrying BRCA1 is much greater than among those carrying BRCA2. "This is of biological interest," he said. "Presumably, it tells us something about the different pathways on which these two genes operate."

Both genes, he said, are known to be involved with repair of DNA, including recognition of breaks in double-stranded DNA and recruitment of other proteins to induce either arrest of cell division and apoptosis, or DNA repair.

Easton and his colleagues plan to examine the pathology of other tumors that occur in people with BRCA1, to find out how similar the tumors are to the breast and ovarian tumors that occur in people with the mutation. This study probably will focus initially on features such as degree of invasion, but may progress to examine genetic changes, such as presence or absence of mutations in the p53 gene. "This could allow us to determine whether these tumors are directly related to the inherited BRCA1 mutations," Easton said.

A national prospective study also is continuing, which will examine how both genetic and lifestyle factors, such as oral contraceptive use and breast feeding, affect the risk of breast cancer and ovarian cancer in those carrying a BRCA mutation.