Gene-expression Profiles of Triple-negative Breast Cancers Differ between African American and Native African Women

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Triple-negative breast cancers in African-American women and native African women have differing gene-expression profiles that may have implications for treatment, according to the first study to directly compare tumor gene expression between these populations. Results were reported at the Fifth American Association for Cancer Research (AACR) Conference on The Science of Cancer Health Disparities, held recently in San Diego.

Investigators led by Lisa Baumbach-Reardon, PhD, an Associate Professor in the Translational Genomics Research Institute (TGen) Integrated Cancer Genomics Division in Phoenix, and Director of the Institute’s DNA Diagnostic Laboratory in Cancer Genomics, performed transcriptome analysis of primary tumor tissue from 9 African American women living in south Florida and 7 African women living in Kenya. All of these women had triple-negative breast cancer without nodal involvement.

A heatmap with hierarchical clustering showed that 8,821 genes were differentially expressed between the two sets of tumors. Fully 60% of these genes were expressed at a lower level in the tumors from the Kenyan women as compared with those from their U.S. counterparts.

Further Study Warranted

“It’s very interesting to be able to directly compare the native Africans to immigrant Africans and see that there have been some influences,” she commented in a press briefing. “We don’t know what they are yet—environment, diet, acculturation.… So what our study suggests is that it just really merits further investigation of larger cohorts of these patients from Africa and U.S. Africans. As we know, overall, African Americans are understudied in many, many trials, including breast cancer, and it’s very difficult to get these kinds of samples to work on from Africa. But we should work globally to collect these samples and to try to analyze them together.”

Additional analyses showed that several of the differentially expressed genes code for proteins lying on DNA repair pathways, according to Dr. Baumbach-Reardon. And one of the genes downregulated in the Kenyan tumors, STAT1, is especially noteworthy in that it has both tumor-suppressor and immune-regulating activities. Levels of expression were six- to sevenfold lower in the Kenyan tumors as compared with the African-American ones.

“This is a very exciting observation,” she commented. “You can imagine a situation where you have a double whammy—where the tumor-suppression function is knocked down or significantly diminished in tumors in Kenyans, plus the immune system is knocked down, which inhibits your immune system to fight off tumor cells. These are preliminary findings and need to be validated in larger cohorts and samples, but we are very intrigued by these results.”

Tailored Therapy

“The differences among women of color in Kenya and in North America are quite tantalizing and suggest that we may need to approach treatment very differently among the women in Kenya vs North America,” proposed William Nelson, MD, PhD, conference Co-Chair, press briefing moderator, and Director of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore.

Research has now identified five to seven genetically distinct variants of triple-negative breast cancer, Dr. Baumbach-Reardon replied. “So I do think that tailored therapy is going to be one of the things that we are all going to be working on in the near future.”

Responsible Factors

Dr. Nelson further wondered if the investigators had observed any phenotypic differences between the African American and Kenyan groups that may provide hints as to why their tumor genetic profiles differ. He noted that some apparent clinical differences may be related in part to the “unholy trinity of poverty, low health literacy, and poor access to health care.”

Teasing out the responsible factors is challenging, Dr. Baumbach-Reardon agreed. The tumors from Kenya tended to have higher grade, to occur at a younger age, and to be of later stage at diagnosis, “so it’s very possible that the metastatic invasiveness of these tumors is worse in Kenya,” she said. “Then we go back to all the sociocultural issues. … Is this late stage because they are delayed in presentation? That’s the same problem we have for African Americans in rural areas here [in the United States].”

Breast cancer mortality is 20% higher for African American women than for their white counterparts, Dr. Baumbach-Reardon noted, giving some background to the study. “From several parts of Africa (Nigeria, Ghana, Kenya), the reports are similar: African women present at a young age with more advanced, late-stage disease.” In addition, “triple-negative breast cancer … is overrepresented in both African Americans and native Africans, as well as in U.S. Hispanic women.”

Noteworthy Merits

The new research has several noteworthy merits, she pointed out. “First, all of the samples were formalin-fixed, paraffin-embedded tissues. We have clearly shown that we can achieve high-quality reproducible data from archived samples, even those from native Africa. Second, all studies were conducted on the same gene-expression platform in collaboration with Alma Diagnostics. Thus, we have direct comparison of data sets. This is the first such study of its kind.”

Taken together, the study’s findings add to accumulating evidence that breast cancer is a heterogeneous disease and underscore the importance of global collaboration in determining why, with the goal of applying that information clinically, Dr. Baumbach-Reardon maintained. “We are just hitting the tip of this iceberg,” she concluded. ■

Disclosure: Drs. Baumbach-Reardon and Nelson reported no potential conflicts of interest.

The project described in this article has been supported by grants from the Department of Defense Synergistic Idea Award No. BC084468, the Susan G. Komen Breast Cancer Foundation, Grant No. POP0601150, Bankhead-Coley Cancer Research Program Award No. 09BW-01-26814, and the Women’s Cancer Association of the University of Miami. This project has greatly benefited from a long-standing collaboration with Almac Diagnostics.