Rectifying a research disparity

New PHS study examines under-studied role of DNA changes in breast-cancer gene susceptibility among African-American women
Dr. Kathleen Malone seated at her computer
Dr. Kathleen Malone co-leads a two-year study designed to rectify the lack of information on BRCA1 and BRCA2 gene mutations among African-American women. The researchers hope their study will hasten the development of breast-cancer risk models for this under-studied group. Photo by Stephanie Cartier

Women considering genetic testing to better understand their lifetime risk of breast and ovarian cancer may find that the results can bring more questions than answers. This problem is even more extreme for African-American women because there are virtually no useful data available to help in the interpretation of test results. A new Center study is poised to change that.

The National Institutes of Health (NIH) recently awarded $198,000 over two years for a translational-research study to provide the missing information. This hopefully will hasten the development of breast-cancer risk models for African-American women. The project is led by Dr. Kathleen Malone in the Public Health Sciences Division, and former Center scientist Dr. Elaine Ostrander, now chief of NIH's Cancer Genetics Branch of the National Human Genome Research Institute.

The majority of breast and ovarian cancers in rare, high-risk families stem from a well-characterized category of mutations in the genes BRCA1 and BRCA2. Women with these types of mutations face a lifetime risk of breast cancer of up to 85 percent and a lifetime ovarian-cancer risk of up to 60 percent. That compares with an approximate average 12 percent lifetime breast-cancer risk and a 1 percent to 2 percent average lifetime ovarian-cancer risk. Although well-studied in high-risk families, the role of BRCA1/BRCA2 in breast cancer in the general population is poorly understood, particularly among older women and African-American women.

Malone, Ostrander, and colleagues recently completed a multicenter population-based study of BRCA1/BRCA2 in 1,628 women with breast cancer and 674 women without breast cancer that presents first-time estimates of prevalence and predictors of mutations in both older women and African-American women. The results appear in the Aug. 15 issue of the journal Cancer Research. The new NIH-funded study extends the previous project and aims to better understand the clinical significance of BRCA1/BRCA2 missense changes in African-American women.

Missense change

The sequence of DNA letters or nucleotide bases in a gene contains the blueprint for making a particular type of protein. The term missense change refers to a single "letter" (or base) substitution in the DNA alphabet, which alters the amino acid, which in turn can cause a variant protein to be formed. The protein may or may not be normal. Thus, missense changes can have effects ranging from partial to complete loss of a protein's biological activity to no functional effect at all. Sickle-cell anemia is an example of a disease caused by a missense change. In sickle cell, a single amino acid change in the hemoglobin gene causes cells to contort. Sickle cell was the first disease shown to relate to a missense change.

Many older technologies rarely detected missense changes, but newer tools are more sensitive. "With newer technologies, we can see these missense changes more readily than before and there are large numbers of them present in these two large genes," Malone said. "Not only are these changes amazingly common, but African-American women have a higher proportion of them compared to Caucasian women."

CARE study

The new work utilizes data from the Women's Contraceptive and Reproductive Experiences (CARE) study, a large population-based study of breast cancer that included more than 9,000 women ages 35 to 64, with and without invasive breast cancer from five U.S. metropolitan areas.

Preliminary analyses of the CARE data revealed a dramatic prevalence of DNA sequence variants (missense changes) of unknown clinical significance in 61 percent of the African-American BRCA2 carriers. "That's a huge proportion," Malone said. "We know many probably have no effect on disease, but some are likely to be deleterious. We don't have the basic-science knowledge of the impact of these changes on protein production. So our mission is to employ a variety of strategies to classify these variants as neutral or adverse in effect."

The research team is in a unique position to tackle this issue. "No one else has been studying these genes in settings with large numbers of African-American women. We are fortunate to have the chance to explore these questions in CARE, which includes the largest ever BRCA1and BRCA2 screening study of African-American women," Malone said.

She said one recent report on these genes drew data from 10,000 largely American women, but fewer than 100 of those were African-Americans. "The striking scarcity of data from African-American women means that when any given African-American woman is tested and found to carry a missense change, there are no data to which her results can be compared in order to determine if other carriers have developed cancer. It's really upsetting to realize how under-studied African-American women are."

The new research, which begins next month, is complicated by the fact that the BRCA genes are very large with thousands of variants dispersed throughout them. It would be an overwhelming task to conduct functional assays on all variants observed, so the researchers must whittle down the big number to something more manageable before pursuing functional lab analyses.

Evolutionary biology approach

Jessica Dolle, an epidemiology student at the University of Washington, will help narrow the field of variants to study by taking an evolutionary biology approach. "We plan to examine each of these missense variants across species to see if they have been present far back in time and across diversity of species," said Malone, who is also a research professor of epidemiology at the UW School of Public Health and Community Medicine. "The ones that have been conserved the most are also the most likely to be functional. That's where a lot of our effort is going to go."

Other study team members include David Doody, who did all the primary statistical work for the CARE study, and Dr. Li Hsu, a Public Health Sciences Division biostatistician who will incorporate these data into models estimating lifetime risk of developing breast cancer, along with Dr. Janet Daling, who was an investigator on the original BRCA1/BRCA2 project.

Once Center researchers come up with a high-priority list of missense-change candidates they think might be functionally important, Ostrander will use yeast-based approaches for the functional assays.

Goal is within reach

The researchers hope the results of their project will form the basis of larger future studies to address related issues, such as the development of improved models of lifetime risk associated with these missense changes and assessment of gene-environment interactions.

NIH's bench-to-bedside research program has been in place since 1999, but this year marks the first time projects in minority health and health disparities have been funded. It is also the first time project teams were open to NIH intramural and extramural collaborators, which proved advantageous to Malone and Ostrander, who have partnered in research for about 12 years.

"This is a project I feel passionate about," Malone said. "This is a glaring need, and someone needs to do this. We're very excited."

"Sometimes in science, we're taking incremental steps toward a goal that's really far away," Malone said. "In this case, I think we're in a position to provide women, clinicians and genetics counselors in the near future with a lot more information about what these missense changes mean. If we can inventory and classify the changes, then eventually we'll be able to assign a likelihood of whether they are related to a high risk or low risk of developing disease. That's our goal, and I think it's achievable."

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