The Link Between African Ancestry & Triple-Negative Breast Cancer : Oncology Times

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The Link Between African Ancestry & Triple-Negative Breast Cancer

Froelich, Warren

doi: 10.1097/01.COT.0000903764.44082.25
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To better understand the biological pathways underlying triple-negative breast cancer (TNBC) among women of African ancestry, a team led by researchers at Weill Cornell Medicine has identified a large set of genes whose expression is shared among an international cohort of women from a cross section of regions and nations.

The researchers, whose findings were published in Cancer Discovery, suggest that the ancestral genetic backgrounds harbored in women of African descent might help explain the prevalence and some of the disparities seen for hard-to-treat aggressive breast cancers observed among African American women (2022; https://doi.org/10.1158/2159-8290.CD-22-0138). If so, these results may open a pathway to identify novel diagnostic and treatment options among women of African descent for these highly aggressive tumors, they noted.

“This (study) presents an amazing opportunity to diagnose and treat this population with better precision—accurate precision medicine,” said principal investigator Melissa B. Davis, PhD, Associate Professor of Cell and Developmental Biology Research in Surgery and Director of Health Equity in the Englander Institute for Precision Medicine at Weill Cornell Medicine.

“This is the first study to use quantified African ancestry to determine ancestry-associated gene expression profiles among a diverse cohort enriched with individuals of African ancestry,” added Rachel Martini, PhD, Postdoctoral Associate in Surgery at Weill Cornell Medicine and the study's lead author.

Study Details

Presented at the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved, the study identified the expression of 613 genes linked to African ancestry and more than 2,000 genes associated with regional African ancestry, in addition to population-level distinctions in immunological landscapes.

Previous studies comparing breast cancer tumors from African American and European women relied on self-reported racial identification (i.e., comparing African American to European American women). However, many women are not aware of the geographical origins of their ancestors nor how much of their DNA was inherited from each source, known as genetic ancestry. This study identified an individual's ancestry not only by African descent, but also by specific regions in Africa, including African/Ghanaian women, East African/Ethiopian women, and African American women.

“Whereas other studies will typically use European African populations as a comparison group, we chose to only focus on individuals of African ancestry, where we observe a range of genetic admixture across the cohort and leverage a patient's admixture to quantify differences in gene expression profiles,” Martini explained. “Using this approach in combination with typical self-reported, race-based categorization has allowed us to define distinct gene and pathway subsets that are unique to ancestry or self-reported race.”

Triple-negative breast cancer is an aggressive subtype of invasive breast cancer that is estrogen receptor-negative, progesterone receptor-negative, and HER2-negative, and clinicians have fewer treatment options to seek out and destroy these tumors. The disease affects a disproportionate number of Black women and contributes to the racial disparities in breast cancer mortality.

While later diagnoses and limited access to treatment options contribute to these poor outcomes, previous studies found that TNBC incidence rates across African nations represent about one-third of all breast cancer diagnoses compared to less than 20 percent in other nations.

Other studies have even revealed a disparity among African women from different regions, with the highest incidence of TNBC in West African nations compared to East African nations. These studies underscore that migration and inter-tribal marriages have yielded a heterogeneous mixture of genetics among African women living in different parts of Africa, Europe, and North America. All this suggests that previous studies of TNBC using self-reported race as its foundation fail to capture the true association of African ancestry with TNBC biology.

Research Specifics

To clarify the genetic influences associated with African ancestry on TNBC, the Weill Cornell-led team chose to first estimate the genetic composition of regional African ancestry, rather than treating continental ancestry as a homogeneous group.

Toward that end, the team analyzed breast tissue samples collected from 132 patients and RNA sequencing on a subset of 26 cases provided by the Englander Institute for Precision Medicine at Weill Cornell Medicine, the University of Alabama at Birmingham, and the International Center for the Study of Breast Cancer Subtypes, who provided samples from The Komfo Anokye Teaching Hospital in Kumasi, Ghana, as well as the St. Paul's Hospital Millennium Medical College in Addis Ababa, Ethiopia.

Their cohort was strategically designed to include patients from distinct regions of Africa to represent the mixed African ancestry of African Americans. “In addition, we filtered out genes that were associated with social constructs, rather than ancestry, to delineate the environmental versus genetic influences underlying these differences,” Davis said.

After identifying the expression of genes linked to African ancestry at the country and regional level, the researchers examined the affected biological pathways and estimated proportions of immune cells in tumors. Women with TNBC with a high degree of African ancestry, primarily East Africans from Ethiopia, had significantly higher immune cell populations infiltrating tumors than women with a lower degree of African ancestry who were mainly African Americans and West Africans from Ghana.

“Pathway analysis of our African ancestry associated genes revealed an enrichment in immune cell trafficking pathways, where increased immune cell infiltration was associated with higher levels of quantified African ancestry,” Martini said.

In a series of validation cohorts, the team showed that this enrichment was driven by an increase in T cells, among other immune subsets, into the tumor microenvironment. The results are of particular interest to researchers studying the benefits of immunotherapy to improve treatment response.

“An assessment of the immunological landscapes must be a key diagnostic test, particularly in this population, but for any patients,” Davis said. “The population-level distinction needs to be further investigated in the clinic, perhaps through immunotherapy paradigms, to trigger better treatment outcomes. At the very least, this should incentivize higher enrollment [and] targeted recruitment of these patients of African descent for immunotherapy trials.”

Martini added, “African ancestry-associated gene expression signatures we've identified in the TNBC tumor microenvironment represent unique targets for future biomarker development or prospective targets for future therapeutics.”

Interestingly, the team also found co-morbidity pathways related to cardiac function, adipose/obesity pathways, diabetes, and insulin signaling among African American patients, but not activated in Ghanian and Ethiopian patients.

“These comorbidities potentially influence the race-specific biological differences of TNBC microenvironments, which we detect in our cohort,” the researchers wrote in Cancer Discovery. “While these comorbidities are known risk factors for negative outcomes, they could be addressed with interventions that target these pathways in tumors.”

Warren Froelich is a contributing writer.

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