Study shows key role of genetics in identifying ancestry-based aspects of cancer, survival

COLUMBUS, Ohio – Researchers at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James) led a global study that identified molecular predictors of survival among Black patients with acute myeloid leukemia (AML). The study suggests a need to modify current AML risk layers by including ancestry-specific genetic factors and testing those in clinical trials.

Co-corresponding authors for study, published in Nature Genetics, are Ann-Kathrin Eisfeld, MD, director of the Clara D. Bloomfield Center for Leukemia Outcomes Research at the OSUCCC – James, and Elaine Mardis, PhD, co-leader of the OSUCCC – James Translational Therapeutics Program.

Study authors note that while many genomic studies over the years have helped scientists classify AML subtypes, the genomic profiles and biomarkers among diverse patients with AML are under studied. This problem has resulted in sustained disparities in survival among patients with this disease.

“We hope our study highlights the need to have more diversity in clinical studies and subsequent biobanking,” said Eisfeld, a hematologist the OSUCCC – James. “There is so much knowledge and improvement in care to be gained for all our patients if we strive toward inclusivity in our efforts. This study is just the first of many steps needed.”

The researchers also stated that, in most cancer genomics-based discovery studies to date, including AML, Black patients account for less than 2% of all patients studied, even though Black patients represent 9% of patients with an AML diagnosis.

“The disparity of AML genomic data between ancestry-diverse populations results in the inequitable application of molecular medicine, which increases the potential for inadequate treatment,” they wrote. “Previous studies showed that self-reported Black patients with AML have inferior outcomes compared with white patients.”

The researchers add that the frequency of genetic mutations and their outcome are different for Black patients with AML.

“The results we’ve reported are striking and emphasize the role genomics can play in identifying ancestry-specific aspects of cancer onset and outcomes,” said Mardis, co-executive director of the Steve and Cindy Rasmussen Institute for Genomic Medicine at Nationwide Children’s Hospital. “Our initial results will require genomic profiling of additional Black AML samples, which is underway thanks to National Cancer Institute funding. Ultimately, changing AML risk stratification based on genetic ancestry will require a conclusive clinical trial, but we feel our report strongly supports that likelihood.”

Study methods and results
In this study, the researchers compared genetic mutation frequencies of 100 Black patients with AML to those of 323 white patients with AML and found that 73% of 162 gene mutations recurrent in Black patients were found in only one white patient or were not detected at all. Other analyses of Black patients found that mutations in NPM1 and NRAS genes were associated with inferior disease-free survival, and mutations in IDH1 and IDH2 genes resulted in reduced overall survival.

Further, inflammatory profiles, cell-type distributions and transcriptional profiles differed between Black and white patients with NPM1 mutations.

When the scientists incorporated these ancestry-specific mutations into the latest European Leukemia Net (an international cooperative research network) genetic risk stratification system, risk group assignment changed for one-third of Black patients, improving their outcome predictions.

This study has shed light on the genomic landscape of AML in Black patients, including the identification of ancestry-associated gene mutations and biological features that differ from traditional European ancestry (white) studies.

Electra Paskett, PhD, deputy director for population sciences and community outreach at the OSUCCC – James, where she also is founding director of the Center for Cancer Health Equity, agrees about the importance of this work.

“This is a landmark study demonstrating the value of including diverse participants in biobanking studies that allow for assessment of genomic factors across race,” said Paskett. “In the future, including other levels of influence on outcomes – like individual risk factors, physical and social context and policy factors – will be important to explain differences that are not explained by genetics.”

Eisfeld and Mardis say they hope this large-scale study of AML patients with African ancestry will set a precedent for future genomic profiling efforts, “as the current underrepresentation of historically marginalized patient populations constrains our ability to provide the best possible care and limits our understanding of AML biology.”

This research was supported in part by the National Cancer Institute of the National Institutes of Health; Coleman Leukemia Research Foundation; Leukemia & Lymphoma Society; American Cancer Society; and the Leukemia Research Foundation. It was jointly sponsored by a Ruth L. Kirschstein National Research Service Award Institutional Predoctoral Training Program in Neurosciences and the D. Warren Brown Foundation.

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