For cancer risk, some BRCA mutations are more dangerous than others

Researchers try to figure out which BRCA mutations result in the greatest risk of breast or ovarian cancer

Doctors have long recognized that women with mutations in two particular genes – BRCA1 and BRCA2 – have a higher risk of breast and ovarian cancer. Now they are starting to figure out which mutations are worse than others.

They have even discovered that some of these mutations may reduce a woman's risk of breast or ovarian cancer to levels much lower than previously thought.

The findings, published in Wednesday’s edition of the Journal of the American Medical Assn., point to a future in which detailed genetic analysis helps patients customize their treatment plans.

“This study is the first step in defining differences in risk associated with location and type of BRCA1 and BRCA2 mutations,” the study authors wrote. “Knowledge of mutation-specific risks could provide important information for clinical risk assessment” that will help women and their doctors determine the best treatment for them.

Everyone carries the BRCA1 and BRCA2 genes. Both genes contain instructions for making proteins that fight tumors by fixing mistakes in DNA. However, some unlucky people – Angelina Jolie among them – have mutations in these genes that make them more prone to breast and ovarian cancers. (They are also more likely to get cancers of the pancreas, prostate, fallopian tubes and peritoneum.)

Experts estimate that from 1 in 300 to 1 in 800 people carry one of these harmful mutations. However, the prevalence is much higher in some populations. Among Ashkenazi Jews, for instance, as many as 1 in 40 have a BRCA1 or BRCA2 mutation, according to the Texas Medical Assn.

As far as researchers can tell, having a BRCA1 mutation increases a woman’s risk of getting breast cancer by the age of 70 from the baseline of 12% to somewhere between 55% and 65%, and a BRCA2 mutation boosts it to 45%. For ovarian cancer, a BRCA1 mutation increases the risk from the 1.3% seen in the general population to 39%, and a BRCA2 mutation raises it to between 11% and 17%.

For the JAMA study, researchers recruited more than 30,000 women from 33 countries on six continents. All of the women had BRCA mutations that are known to increase cancer risk. (To avoid confusion, 84 women who had both BRCA1 and BRCA2 mutations were excluded from the analysis.) More than 90% of the study participants were white, and nearly 10% of them were Ashkenazi Jews.

The researchers grouped the women into “bins” based on where their mutations appeared in the genome. Then they looked to see how many women in each bin were diagnosed with breast and/or ovarian cancer while they were being tracked.

Overall, the researchers found that 46% of the 19,581 women with a BRCA1 mutation were diagnosed with breast cancer, 12% were diagnosed with ovarian cancer, 5% got both and only 37% remained cancer-free. The average age at diagnosis was 39.9 years for breast cancer and 50 for ovarian cancer.

Among the 11,900 women with a BRCA2 mutation, 52% got breast cancer, 6% got ovarian cancer, 2% got both and 40% got neither during the course of the study. In this group, the average age at diagnosis was 42.8 years for breast cancer and 54.5 years for ovarian cancer.

Most important, the researchers found that when it comes to cancer risk, not all BRCA mutations are created equally. For instance, among the women with BRCA1 mutations, those who had a small glitch that caused a protein to have the wrong amino acid saw their risk of getting breast cancer by age 70 jump from 59% to 69%, they estimated. The same was true for women with mutations that caused the gene to skip some steps in making a protein, or that had a mutation associated with Jewish heritage.

In addition, women with a BRCA1 Jewish mutation had a relatively low 26% risk of ovarian cancer.

For women in the BRCA2 group, those who had a particular kind of mutation that caused the protein to be truncated had a relatively low 40% risk of breast cancer by age 70. Also, women with mutations that didn’t cause the gene to build incomplete proteins had a 3% risk of ovarian cancer, according to the study.

The researchers emphasized that these risk estimates are not exact because they don’t take into account a specific woman’s family history and other factors that influence life expectancy.

They also noted that their results may not generalize to all women with BRCA1 and BRCA2 mutations, but it should be representative of such women who sought out genetic testing.

“With appropriate validation, these data may have implications for risk assessment and cancer prevention decision making among carriers of BRCA1 and BRCA2 mutations,” they concluded.

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