Research & Clinical Trials

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Research & Clinical Trials > Research Findings > Risk of Breast and Ovarian Cancer

Risk of Breast and Ovarian Cancer is Associated with the Type and Location of BRCA Mutation

by Lisa Rezende, PhD

What is the risk of breast and ovarian cancer for a BRCA1 or BRCA2 mutation carrier? While this sounds like a simple question, calculation of lifetime risk requires large studies and sophisticated statistical analysis. Most people who discover that they carry a BRCA mutation are given risk estimates by their genetics professional and/or the laboratory reporting the mutation. However, most mutation carriers know that even within their own families, the types of cancers and age of onset can vary. Researchers are working towards understanding how to best predict the actual risk of cancer for mutation carriers. A new study published in the Journal of the American Medical Association by Timothy Rebbeck, Ph.D., and colleagues shows that one factor that might be useful in predicting cancer risk is the type and location of the mutation.1

Using data from an international collaboration of research centers, the Dr. Rebbeck and his collaborators studied the health histories of 19,581 women with BRCA1 mutations and 11,900 women with BRCA2 mutations.

Among BRCA1 mutation carriers:

  • 9,052 had breast cancer (46%)
  • 2,317 had ovarian cancer (12%)
  • 1,041 had both breast and ovarian cancer (5%)

Among BRCA2 mutation carriers:

  • 6,180 had breast cancer (52%)
  • 682 had ovarian cancer (6%)
  • 272 had both breast and ovarian cancer (2%)

This data was then used to calculate the risk of breast and ovarian cancer for two different criteria: the location of a mutation within the gene and the type of mutation.

To study whether or not the location of the gene mutation affected cancer risk, the researchers divided each gene into regions, and then calculated the relative risk for cancer for someone with a mutation in that region. Using this method, they were able to show that breast and ovarian cancer risk varies depending on the location of the mutation. Specifically, they were able to define �breast cancer cluster regions� (BCCRs) where the relative risk of breast cancer was higher than the relative risk for ovarian cancer. Similarly, they were able to identify �ovarian cancer cluster regions� (OCCRs) where the relative risk of ovarian cancer was higher than the relative risk of breast cancer. In other regions of the gene involved, the relative risk of breast cancer was similar to the relative risk of ovarian cancer, and was not considered to be a cluster. BCCRs and OCCRs were found in regions of both the BRCA1 and BRCA2 genes.

Type of Mutation:
Researchers also analyzed cancer risk by the type of mutation. This is particularly significant, because BRCA1/2 genes issue instructions for making BRCA1 and BRCA2 proteins. Mutations are mistakes in those instructions, and different types of mistakes produce different consequences. The researchers also found that different types of mutations were associated with different risk of breast and ovarian cancer.

This important research shows that the risk of cancer varies depending on the type and location of mutation in BRCA1 and BRCA2 mutation carriers, critical knowledge for improving how we assess cancer risk. The current study calculated cancer risks for the three Ashkenazi Jewish founder mutations; future publications from this research team will be able to describe that cancer risks for many more mutations in BRCA1 and BRCA2. This exciting new research shows that in future, we will more individualized estimates for cancer risks. For today, however, clinical guidelines remain the same. Even when exact risk estimates for each mutation becomes available, members of our advisory agree the best way to understand your personal risk for cancer and to learn about risk-management options is to meet with a genetics expert.

For more information on this emerging research on risk assessment, watch Dr. Timothy Rebbeck�s presentation from the �What�s New in HBOC Research?� session at the 2014 Joining FORCEs conference. Dr. Rebbeck, co-researcher Dr. Katherine Nathanson, and other faculty from the Basser Research Center for BRCA will speak at this year�s Joining FORCEs Conference in Philadelphia on June 19th and 20th.


1. Rebbeck TR, Mitra N, Wan F, et al. �Association of Type and Location of BRCA1 and BRCA2 Mutations with Risk of Breast and Ovarian Cancer.� Journal of the American Medical Association (2015) Vol. 313, No. 13, pp. 1347-61.

posted April 11, 2015

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