A look at how BCRF investigators are unraveling the role of family history, race, ethnicity, and more to improve breast cancer detection and prevention

Most people who develop breast cancer have no family history of the disease, but that’s not always the case. An individual’s family history, genetics, race, and ethnicity are all important factors that can contribute to their breast cancer risk.

This year, BCRF is investing more than $6 million to understanding the root causes of breast cancer. Half of this investment is committed to defining how inherited mutations, race, and ethnicity influence breast cancer risk and identifying ways to reduce breast cancer among high-risk groups.

Understanding BRCA Mutations

An estimated 10 to 15 percent of breast cancers are thought to be caused by inherited genetic factors that are passed from generation to generation through our DNA. These include changes in a person’s genetic code that severely affect normal functioning of a gene. The most common and best-known genes associated with a higher risk for breast cancer are the BRCA1 and BRCA2 genes.

In landmark discoveries in the 1990s, BCRF investigators Drs. Mary-Claire King, Alan Ashworth, and their colleagues identified BRCA1 and BRCA2, respectively. These findings launched new avenues for research that propelled our understanding of hereditary breast cancer—and led to the development of genetic tests that are in use today.

In the general population, about 12 percent of women in the U.S. will develop breast cancer in their lifetime. By contrast, about 72 percent of those with a BRCA1 mutation and about 69 percent of those with a BRCA2 will develop breast cancer by the age of 80. In men with BRCA2 mutations, the risk of developing breast cancer increases to 8 percent (compared with 0.1 percent in the general population).

Uncovering BRCA Mutations by Race and Ethnicity

While BRCA mutations are rare, certain populations have a much higher risk of inheriting one. In those with Ashkenazi Jewish (Eastern European) heritage, the chance of inheriting a BRCA gene mutation is 1 in 40, compared to 1 in 500 in the general population. In Jewish people of Ashkenazi descent, BRCA mutations are responsible for 10 percent of breast cancer and 40 percent of ovarian cancer cases.

In a groundbreaking project—the New York Breast Cancer Study—led by Dr. King, 1,007 Ashkenazi Jewish women with breast cancer were tested using a multigene panel. The team found that among this population, approximately 11 percent of all breast cancers are caused by one of only three BRCA1 or BRCA2 mutations, while one percent of those tested carried mutations in other known breast cancer genes (mostly CHEK2). This study supported screening in the Ashkenazi Jewish population and inspired BCRF investigators Drs. Susan Domchek, Kenneth OffitKatherine Nathanson, and Judy Garber to develop and test a novel screening program in women and men with Ashkenazi ancestry in the U.S. to identify families at risk of breast and other cancers.

Less is known, however, about the prevalence of BRCA mutations in other populations, making this a research priority. BCRF investigators Drs. King, Ephrat Levy-Lahad, and Moien Kanaan have conducted genetic testing in 1,300 breast cancer patients of Arab ancestry—the largest cohort of Arab women in the world to participate in cancer genetics testing. As a result of their BCRF-supported research, genetic testing and counseling is now routine for breast cancer patients at most major Palestinian hospitals.

Studies on breast cancer–associated genetic mutations have typically been conducted in white women, leaving a big question mark as to whether women of color are affected similarly. To address this disparity, BCRF investigators have led the way by conducting studies involving Black and Hispanic women.

  • Dr. Olufunmilayo Olopade has worked to mainstream genetic testing for BRCA1 and BRCA2 gene mutations and extend its use to Black women. This is particularly important, as Black women are disproportionately diagnosed with aggressive triple-negative breast cancer (TNBC), the most commonly diagnosed breast cancer in BRCA1 mutation carriers.
  • Drs. Fergus Couch, Christine Ambrosone, Nathanson, Domchek, and colleagues examined the link between genetic mutations and breast cancer risk in Black women. Comparing genetic data from 5,054 Black women with breast cancer to 4,993 unaffected Black women, the researchers found that mutations in BRCA1, BRCA2, and other genes were associated with high and moderate risk of the disease in this population.
  • In BCRF-funded studies, Dr. Jeffrey Weitzel developed a genomic cancer risk assessment tool to evaluate BRCA-associated breast and ovarian cancers in Hispanic women and Latinas. Through these studies, he discovered a distinct BRCA1 mutation that may have originated in Mexico.

Investigating Genetic Mutations Beyond BRCA 

BRCA mutations account for only 5 to 10 percent of hereditary breast cancers. Through the aforementioned New York Breast Cancer Study, Dr. King and her colleagues showed that mutations in CHEK2 double a person’s risk of breast cancer—a significant increase, but not nearly as severe as the more than ten-fold increase due to BRCA1 or BRCA2 mutations.  Other work by BCRF researchers Drs. Offit, Couch, Mark Robson James Ford, and their teams, has enriched our understanding of inherited risk, expanding it to include mutations in genes including PALB2, BARD1, TP53, ATM, and many more that are still being studied.

Dr. Couch has also led several large studies that yielded the first-ever estimates of breast cancer risk for women of different races and ethnicities with inherited gene mutations other than BRCA1 and BRCA2. In one study, his team, which included BCRF investigators Drs. Priyanka Sharma and Garber, assessed genes in more than 10,000 people with TNBC and found mutations in BARD1, BRCA1, BRCA2, PALB2, and RAD51D were associated with a high risk of TNBC, while BRIP1, RAD51C, and TP53 mutations were associated with moderate risk. These results were similar in Black and white women.

In early 2021, Dr. Couch and fellow BCRF investigators Ambrosone, Nathanson, and Domchek published the results of the first large study to examine inherited mutations in breast cancer susceptibility genes in women without a family history of the disease (previous studies had focused on high-risk populations). Analyzing DNA from 32,247 women with breast cancer and 32,544 unaffected women yielded several important insights. Among them:

  • While the risk of developing breast cancer is generally lower for women without a family history of the disease, 30 to 50 percent of breast cancer mutations occur in women who have traditionally not been considered high risk.
  • Although uncommon, specific gene mutations in the BARD1, RAD51C, and RAD51D genes were associated with an increased risk of estrogen receptor (ER)–negative breast cancer and TNBC, and they and were more frequent in Black women.
  • Mutations in ATM, CDH1, and CHEK2 were linked to an increased risk of ER-positive breast cancer and more frequent in non-Hispanic white women.

These studies provide new insight into differences in specific gene mutations associated with race as well as breast cancer subtype.

Looking forward

BCRF researchers are continuing to conduct numerous ongoing investigations into inherited mutations. Among some of the notable projects we are supporting:

  • Dr. Robert Vonderheide is testing a breast cancer prevention vaccine in healthy women who carry a BRCA mutation.
  • Drs. Dezheng Huo and Olopade are conducting studies identifying genetic factors responsible for TNBC and those that specifically predispose Black women to this aggressive form of the disease. 
  • Dr. David Cortez is focusing his research on understanding the full network of factors involved in BRCA1 and BRCA2 associated breast cancer to define those that are responsible for treatment resistance. 
  • Dr. Ashworth has identified several candidate genes that cause BRCA mutant cancer cells to become resistant to treatment and is characterizing these genes to determine methods to disrupt that process.
  • Dr. Robson is evaluating whether polygenic risk scores (a number that considers all of a person’s genetic variants) can help women with mutations in BRCA1 or BRCA2 make clearer decisions about their health.

These are a few highlights of how BCRF is investing in this area of research and funding research that has already advanced screening and genetic testing. Other BCRF studies are examining the underlying mechanisms of hereditary breast cancer and deciphering key biological and molecular steps that are involved. With this depth and breadth of research, BCRF’s investment potentially provides a myriad of benefits for those facing a high risk of developing breast cancer—from improved screening, risk management, and cancer prevention strategies to specific targeted therapies to improve outcomes.

A version of this article was published on September 24, 2019. This piece has since been updated.

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