BioWorld International Correspondent

LONDON Scientists have, at long last, identified a third gene that influences a woman’s risk of breast cancer. The gene appears to act in the same biochemical pathway as the two previously identified breast cancer genes, BRCA1 and BRCA2.

Unlike BRCA1 or BRCA2, however, women who inherit the mutant version of CHEK2 have a much lower risk of developing breast cancer. Only about one in five will do so but still double the population risk, which is one in 10.

The CHEK2-Breast Cancer Consortium, which has members in the Netherlands, the UK, Germany, Canada, Israel, the U.S. and France, reports its findings in a paper in the April 22, 2002, online publication of Nature Genetics titled “Low-penetrance susceptibility to breast cancer due to CHEK2*1100delC in noncarriers of BRCA1 or BRCA2 mutations.”

Nazneen Rahman, senior lecturer in cancer genetics at the Institute of Cancer Research in Sutton, told BioWorld International: “Scientists have suspected that genes conferring an increased but low risk of cancer exist, but this is the first study to confirm the existence of such a gene. It also gives us new insights into the pathways involved in breast cancer, which in the long term may be helpful in developing new treatments.”

Women in families affected by multiple cases of breast cancer that are not caused by BRCA1 or BRCA2 may want to find out if their family is one in which inheritance of mutant CHEK2 plays a part, in order to help them come to a more informed decision about what course to take, Rahman said. “But we have to be careful because we know that many people who have this mutation will not develop breast cancer even if they are from families with many cases of breast cancer.”

Doug Easton, another member of the consortium based at the Cancer Research UK Genetic Epidemiology Unit in Cambridge, UK, said, “This is a very important discovery. We believe that CHEK2 is involved in repairing genetic damage within a woman’s breast, which is why her risk of cancer goes up when the gene goes wrong. By identifying genes that work in combination to raise the risk of breast cancer, we will gain a much clearer understanding of how the disease develops.”

The consortium studied families containing multiple cases of breast cancer that were known not to be caused by either BRCA1 or BRCA2. In the largest family, a region of chromosome 22q appeared to be inherited more often by individuals who had breast cancer than by those who were unaffected.

The team therefore decided to investigate the CHEK2 gene, which is present on chromosome 22q, as it was known to be the human equivalent of genes that, in yeast, encode proteins that prevent cells from dividing if their DNA has been damaged. Other researchers had also shown that a mutation of the CHEK2 gene, known as *1100delC, stopped the protein from carrying out that function.

Extensive tests carried out by the consortium showed that CHEK2*1100delC was present in 1.1 percent of 1620 normal (control) individuals, and in 5.1 percent of 1071 individuals with breast cancer from 718 families known not to be carrying BRCA1 or BRCA2.

Mutant CHEK2 also plays a role in male breast cancer and ovarian cancer. It was present in 13.5 percent of individuals with breast cancer from non-BRCA1, non-BRCA2 families that had one or more individuals with male breast cancer, and in 4.3 percent of individuals from similar families that had one or more individuals with ovarian cancer.

When the researchers looked for mutant CHEK2 in families with multiple breast cancer cases caused by BRCA1 or BRCA2, however, they found that there was no statistically significant difference between the frequency of the CHEK2 mutation in that group than in the general population.

“This tells us that if you already have either a BRCA1 or a BRCA2 mutation, then having CHEK2 as well does not put you at any additional risk of developing breast cancer,” Rahman said. “We know that BRCA1, BRCA2 and CHEK2 are all probably acting in the same pathway that is involved in repairing damaged DNA. If you have mutations in BRCA1 or BRCA2, that pathway is already broken, so another mutation within it has no additional effect.”

She and her colleagues are now embarking on studies to identify further families with the CHEK2 mutation. “We want to look at whether their cancers are different in any way and if they respond to treatment differently,” she said.