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AACR Researchers Emphasize Importance of Genetic Ancestry as Factor in Breast Cancer Studies

CHICAGO (GenomeWeb) – The importance of diversity in genetic studies of cancer continued to be a crucial theme at the annual meeting of the American Association for Cancer Research in Chicago this year.

Researchers at the AACR annual meeting in Washington, DC in 2017 addressed the lack of diversity in many large genomic datasets, presenting findings which showed that this could be hindering efforts to lower the rates of cancer-related deaths.

At a session Sunday on genetic ancestry and breast cancer risk, the issue was further considered as researchers attempted to answer questions regarding disparities in breast cancer outcomes and variations in breast cancer phenotypes associated with race. These variations can be explained not only by environmental, lifestyle, and socioeconomic factors, but by inherited susceptibility as well, the scientists explained.

But the methods for defining racial identity are inconsistent and can lead to gaps in knowledge when it comes to figuring out which genetic mutations can lead to breast cancer in which populations.

For example, explained University of California, San Francisco Associate Professor Laura Fejerman, when considering how genetic ancestry, nationality, and ethnicity affect breast cancer risk for women of Latin-American origin, the term "ethnicity" is not well defined and shouldn't be used. The term "Hispanics" could include people from Spain, for example, while the term "Latinas" could include Brazilians, Guyanese women, or women from Suriname. Meanwhile, Cubans, Argentinians, and Mexicans could fall in the middle.

Instead, she said, researchers should talk about people from Latin America by the country they come from, or if they're in the US, by the country of their ancestry. And even within those countries, Fejerman said, there are diverse populations. While there might be some geographical or environmental factors they share that might be relevant for cancer research, there is great diversity including for genetic ancestry.

"In Latin America, you have a very diverse distribution of ancestral components," she said, pointing to an admixture of indigenous American, African, and European ancestry groups in various countries throughout the region, which means that when researchers are looking at breast cancer, they must take diversity into account.

In fact, Fejerman said, the incidence of breast cancer is very different in different Latin-American countries. In the US, it is noted that Latin-American women have a lower incidence of breast cancer than other populations, but that's only true in Latin American women with certain genetic backgrounds. In certain Latin-American countries, she added, the incidence and mortality rates from breast cancer are higher than in the US.

Fejerman described the latest GWAS study she and her colleagues conducted at UCSF, in which they replicated an earlier study done in 2014 where they found a variant in the 6q25 region that was protective against breast cancer. The signal was strongest in Latina women, Fejerman said. In the most recent iteration of the study, the team found a new variant in the same region in the Estrogen Receptor 1 gene that has not been reported before. Both variants have shown to be protective against ER-negative breast cancer.

The first variant correlates to indigenous Latin-American genetic ancestry. The new variant is found in very low frequency in women of European ancestry, so a GWAS with a high number of patients of European ancestry would not have picked it up. The variant was also replicated in African and Asian populations, Fejerman said.

"We can't move forward with precision medicine without acknowledging that we have this diversity in the world," and studying it in a refined manner, she added. "Ethnicity" is not useful, and cancer statistics based on categories such as Hispanic or Latino should be taken as a first step in health disparities research only.

Meanwhile, Boston University's Julie Palmer discussed African ancestry and breast cancer risk, noting that even within the African continent, women from West and East Africa have different patterns of tumor subtypes. In the US, researchers have found that African-American women exhibit genetic susceptibility to breast cancer subtypes that is similar to that exhibited by women in West-African countries. This can be traced back to their West-African heritage, and it is logical to assume that particular genetic ancestry is dominant in African-American women because West-African women were mainly brought to the US through the slave trade, Palmer said.

In focusing on why African-American women have higher incidences than any other group of triple-negative breast cancer (TNBC) at every age, she said, her research has shown that while some of that is due to factors such as access to care, much of it is due to genetics. In order to determine whether there are specific genomic regions involved that have not previously been identified in GWAS that could explain this difference, Palmer and her colleagues started the AMBER consortium – a collaboration combining data, biospecimens, and expertise from four of the largest studies of breast cancer in African-American women: the Carolina Breast Cancer Study, the Black Women's Health Study, the Women's Circle of Health Study, and the Multi-Ethnic Cohort.

They then added the African-American Breast Cancer GWAS Consortium and the Genome-Wide Association Study of Breast Cancer in the African Diaspora Consortium for a total of 6,657 cases and 7,713 controls. The study did find a novel SNP possibly having some biological relevance to breast cancer in African-American women, Palmer said. Importantly, it also confirmed another SNP in the TERT gene that is the best indicator of risk for ER-negative breast cancer — that risk allele's frequency is twice as high in people of African ancestry as in people of European ancestry and may contribute to higher frequency of ER-negative breast cancer and TNBC in African-American women.

A much larger effort funded by the NCI is now underway, Palmer said. It includes about 20,000 cases and about the same number of controls.

She also noted that her group is currently conducting research on whether immune factors related to ancestry could contribute to more aggressive cancers in African-American women. Her team assayed serum samples from black women and white women and analyzed their cytokines. In data that has yet to be published, they found that CCL2 and CCL11 were significantly different between the two populations and found a SNP near the DARC gene which is evolutionarily conserved. A null allele for the gene, which encodes a glycosylated membrane protein and a non-specific receptor for several chemokines, is fixed in West-African populations and is non-existent in other populations, Palmer said. What this has to do with breast cancer is unclear as of now, she added, but research is ongoing.

Melissa Davis, a researcher affiliated with Henry Ford Health Systems, was a little more detailed about the possible effects of the DARC gene on breast cancer. DARC is expressed in epithelial cells in breast tumor cells, she said.

She described for the first time research that shows how the gene may affect tumor status in African-American women, noting that while her research has shown that tumors from African-American women have no or very little DARC expression, she has also found that DARC expression is associated with higher survival, including relapse-free survival.

Tumors that are low in DARC expression are also low in CCL2 expression, she added, and low levels of CCL2 are associated with low survival.

Genotype and phenotype data indicate that people of African ancestry have a distinct immune regulation in several contexts, including cancer, Davis said, and African-specific alleles are associated with unique regulation of immune-related genes. The dispersal of African-specific genes across the African diaspora has created distinct genetic backgrounds in admixed populations such as African Americans, she added. And these alleles are causing very specific immune responses. Ignoring the genetic diversity behind these responses has helped to drive the disparities of clinical outcomes, and the trend must be reversed, she said.