Breast cancer will likely affect one in eight women at some point during their lifetime, and the risks increase with age. However, the risk is not the same for all women in any given age group.

Genetic changes, including BRCA1 and BRCA2, are known to carry a higher risk, but now scientists say that even family members who test negative for the genetic differences are still at an increased risk of developing the disease.

The discovery of mutations on the BRCA genes has prompted many women to take drastic preventative measures, including Angelina Jolie and Sharon Osbourne, who sought double mastectomies when it was confirmed they had the breast cancer gene.

Now, a new study, published in Cancer Epidemiology, Biomarkers & Prevention, challenges the belief that a woman from a BRCA family who tests negative for her family-specific BRCA mutation has the same chances of contracting the disease as someone in the general population.

Lead author of the research Dr. Gareth R Evans, honorary professor at the Manchester Academic Health Centre at the University of Manchester, UK, explains:

"We found that women who test negative for family-specific BRCA2 mutations have more than four times the risk for developing breast cancer than the general population. We also found that any increased risk for breast cancer is largely limited to BRCA2 families with strong family history and other genetic factors."

He believes there are other genetic factors that may increase the risk of breast cancer.

"It is likely that these women inherit genetic factors other than BRCA-related genes that increase their breast cancer risk," Dr. Evans continues.

"About 77 single nucleotide polymorphisms [SNPs - genetic variations that can help track the inheritance of disease genes within families] are linked to breast cancer risk. Identification of additional SNPs is necessary to understand why some of the BRCA-negative women from BRCA families are at higher risk."

Twice as many cases as expected

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Some women, especially those from BRCA2 families, may test negative to the mutated gene but still develop breast cancer.
Dr. Evans and his team analyzed data collected for the M6-Inherited Cancer in England study, which has screened families of people with breast and/or ovarian cancer for BRCA1 and BRCA2 mutations since 1996.

From the details, the researchers identified 807 BRCA families, including information about whether or not relatives had been tested.

Using this data, researchers found that 49 women who had tested negative for the BRCA mutation had subsequently developed breast cancer.

Even when the researchers factored in age, they found that in each age group, there were about twice as many cases of breast cancer as would be expected within the general population.

Of the 49 women, 22 were among 279 women who tested negative from BRCA1 families, and 27 were among the 251 women who tested negative to BRCA2 mutations.

The study authors then conducted risk analysis, calculating the "observed versus expected ratio" (O/E), the risk of breast cancer in BRCA-negative women from BRCA families, compared with the expected risk in the general population.

They found that the women from BRCA1 families did not experience any increased risk, but the O/E for women from BRCA2 families was 4.57 - leading to the conclusion that BRCA-negative women from BRCA2 families face a fourfold increased risk of developing breast cancer.

When asked what women who had tested negative previously should do now, Dr. Evans told Medical News Today that if there is a strong family history of breast cancer in a BRCA 2 family, for example with a mother and sister diagnosed under 50, they should seek additional screening.

However, he cautioned:

"Screening with MRI is very effective for breast cancer but for ovaries we would advise carriers to have surgery aged 35-40 years or when their family is complete."

Medical News Today reported that levels of female hormones may explain the increased cancer risk among BRCA carriers.