Study identifies genetic factors crucial in acute myeloid leukemia survival in black patients

Researchers led a global study that identified molecular predictors of survival in Black patients with acute myeloid leukemia (AML). The study suggests the need to modify current AML risk levels by including ancestry-specific genetic factors and testing them in clinical trials.

Co-corresponding authors of the study, published in Natural geneticsare Ann-Kathrin Eisfeld, MD, director of the Clara D. Bloomfield Center for Leukemia Outcomes Research at the Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James) – James, and Elaine Mardis, Ph.D., co-leader of the OSUCCC-James Translational Therapeutics program.

The authors note that although many genomic studies over the years have helped scientists classify AML subtypes, genomic profiles and biomarkers among diverse AML patients are understudied. This problem has led to persistent disparities in the survival of patients with this disease.

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

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

“The disparity in AML genomic data between populations of diverse ancestry results in inequitable application of molecular medicine, which increases the risk of inadequate treatment,” they wrote. “Previous studies have shown that self-reported black patients with AML have worse outcomes than white patients. »

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

“The results we reported are striking and highlight the role that genomics can play in identifying ancestry-specific aspects of cancer onset and outcomes,” said Mardis, co-executive director of the 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. Ultimately, changing AML risk stratification based on genetic ancestry will require a conclusive clinical trial, but we believe our report supports strongly this probability.”

Study methods and results

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

Additionally, inflammatory profiles, cell type distributions, and transcriptional profiles differed between black and white patients with NPM1 mutations.

When scientists incorporated these ancestry-specific mutations into the latest genetic risk stratification system from the European Leukemia Net (an international cooperative research network), the risk group assignment changed for a third of black patients, thus improving their forecast results.

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

Electra Paskett, Ph.D., associate director of population sciences and community outreach at OSUCCC-James, where she is also founding director of the Center for Cancer Health Equity, agrees on the importance of this work.

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

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