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Penn Research Suggests More Diversity Needed in Genomic Studies of Breast Cancer


NEW YORK (GenomeWeb) – New research conducted at the University of Pennsylvania suggests that mutations that are predisposing to breast cancer may be different in individuals depending on their ethnicity, and that more diversity is needed in genomic studies to identify population-specific variants.

The University of Pennsylvania researchers in conjunction with researchers at the Karmanos Cancer Center at Wayne State University analyzed 19 genes of 736 women in three patient groups: African-Americans with cancer, African-Americans without cancer, and Caucasians without cancer. They ran a 19-gene next-generation sequencing panel offered by the firm Color Genomics that analyzes genes related to inherited breast cancer, such as the BRCA1 and BRCA2 genes, to get an idea of whether African-American patients may have different variants that play a role in hereditary breast cancer.

Payal Shah, an assistant professor of medicine at the University of Pennsylvania who presented the work at the San Antonio Breast Cancer Symposium earlier this month, said in an interview that the study was a proof of principal designed to get an idea of ethnicity-related differences.

Most genomic studies of inherited breast cancer have been done in Caucasian patients, Shah said. "But, it's possible that different ethnic groups will have different factors that predispose them to cancer. We wanted to understand the differences that play out in breast cancer," she said.  

Other researchers have highlighted the importance of doing genomic studies in diverse populations. For instance, a group that generated an Asian reference genome identified more than 11,000 novel structural variants, including many that seemed to be specific to Asian populations. Groups studying the impact of returning clinical sequencing results have found that there are many more variants of unknown significance found when sequencing individuals who are not of European descent, since those populations are underrepresented in genomic studies.

Understanding population-specific variants is particularly important when considering inherited diseases. African-American women are more likely to be diagnosed with breast cancer before the age of 45 and are more likely to die of breast cancer than Caucasian women, Shah said. Because early-onset cancer is suggestive of a genetic predisposition, it is important to understand the spectrum of inherited variants that play a role.

For instance, a recent study led by Ohio State researchers and published in JAMA Oncology found that that around 16 percent of colorectal cancer patients under the age of 50 had a hereditary cancer mutation, many of which had important implications not only for the individual patient, but also for the patient's family members, in terms of further testing that could potentially lead to earlier diagnosis.

In the University of Pennsylvania study, the researchers found that while the variants in the BRCA1 and BRCA2 genes were pretty similar in the African-American cohort to what has previously been reported from Caucasian individuals, African-American women tended to have fewer mutations in the CHEK2 gene and more mutations in the TP53 gene. In addition, variants of uncertain significance were more prevalent in African-American women. Of the women without cancer, 15 percent of the African-American women contained a VUS compared to 11 percent of Caucasian women.

Shah said the research would serve as a "baseline study, to generate hypotheses" for additional studies. For instance, she said, one interesting next step would be to compare findings in African-American patients with cancer to Caucasians or other ethnic groups who also had cancer to see what variants are common between the two groups and which ones are unique. In the current study, the data from the Caucasian women is only from those without cancer and used as a control, Shah said.

In addition, although the targeted panel that was used was "comprehensive in terms of containing the genes that we are confident are associated with inherited breast cancer, in the future studies may make use of even broader panels," she said.

Another important aspect will be to confirm the findings that the CHEK2 gene may play less of a role in African-American patients and that the TP53 gene may play more of a role. Larger studies will be needed to confirm those findings.

In addition, the VUS found in the African-American patients also warrant further study, particularly since some of those could be pathogenic and potentially help explain the higher rates of earlier age of onset of breast cancer among African-American women.

Shah said that the researchers don't have specific plans to follow up on individual VUS, but they do participate in large-scale national and international efforts to deposit variants into databases and partner with other institutions to determine the significance of the mutations. "We need as much data as we can get," Shah said.

She added that although the current study is too preliminary to have any impact on patient treatment and management, studies like this one could help lay the groundwork for genetic testing in the future. "It could potentially inform how we think about panel testing and what genes to take a close look at when we have a patient who is African-American," Shah said.