Genetic ancestry associated with molecular subtypes, prognosis for childhood ALL

April 18, 2022

4 min read

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Information:
Yang reports grants from the NIH during the conduct of the study and from the NIH outside of the work submitted, as well as a patent application for the Methods for Determining Benefit of Chemotherapy. Please see the survey for all other authors’ relevant financial information. Rabin does not report any relevant financial information.


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Acute lymphocytic leukemia molecular subtypes and prognosis appeared to be linked to genetic origin, suggesting a possible genetic basis for racial and ethnic inequalities in ALL, according to a study in JAMA Oncology.

“It is very clear that ALL biology in childhood differs by genetic origin, and the biology of this childhood cancer has a wide global diversity,” Shawn HR Lee, MD, postdoc Fellow, and Jun J. Yang, PhD, Vice President of the Department of Pharmacy and Pharmaceutical Sciences, both at St. Jude Children’s Research Hospital, Healio said in a joint statement.

ALL compounds with genetic origins.

Data derived from Lee SHR, et al. JAMA Oncol. 2022; doi: 10.1001 / jamaoncol.2021.6826.

“In the past, we have always extrapolated treatment protocols developed for white children (children of European descent) to other population groups,” they continued. “In an era of personalized medicine, we need to develop biologically driven treatment protocols that also take this racial diversity into account and stop assuming that what works for white children will also work for children from other populations.”

Method

The analysis included 2,428 children and adolescents with ALL (mean age 7.8 years; 57.8% men; 70.2% aged 1 to 9 years) from the United States, Southeast Asia (Singapore and Malaysia) and Latin America (Guatemala) enrolled in the frontline clinical trials between March 1, 2000 and November 20, 2020.

Shawn HR Lee, MD

Shawn HR Lee

Lee, Yang, and colleagues performed RNA sequencing to comprehensively categorize molecular subtypes of ALL and genetic origin. They then evaluated associations of genetic ancestors with ALL molecular subtypes and treatment outcomes.

The researchers tried to characterize the diversity of ALL biology (i.e., molecular subtypes) across different global populations and determine whether genetic ancestry affects outcome, even with modern therapy.

Key findings

The results showed that eight of the 21 identified ALL subtypes had an association with ancestry.

Within the individual populations, researchers reported:

East Asian ancestry had a positive association with somatic DUKE4 (OR = 1.3; 95% CI, 1.16-1.45) and ZNF384 (OR = 1.4; 95% CI, 1.18-1.66) gene rearrangements and a negative correlation with BCR-ABL1-like ALL (OR = 0.79; 95% CI, 0.66-0.92) and T cell ALL (OR = 0.8; 95% CI, 0.71-0.9).

Native American descent had a positive attachment to CRLF2 arrangements (OR = 1.48; 95% CI, 1.29-1.69). ETV6-RUNX1 fusion became less frequent as the percentage of Native American descent increased (OR = 0.8; 95% CI, 0.7-0.91), with the opposite trend observed for ETV6-RUNX1-as EVERYTHING.

Children of African descent (OR = 1.22; 95% CI, 1.07-1.37) had a marked predominance of T cell ALL compared to those with a high percentage of Native American descent (OR = 0.53; 95 % CI, 0.4-0.67).

African ancestry had a positive attachment to TCF3-PBX1 (OR = 1.49; 95% CI, 1.25-1.76) and a negative correlation with DUKE4 rearrangements (OR = 0.7; 95% CI, 0.48-0.93; P = 0.01) and hyperdiploidy (OR = 0.77; 95% CI, 0.68-0.86).

As continuous variables, for each 25% increase in descent, African and Native American descent was associated with poorer EFS (African descent: HR = 1.2; 95% CI, 1.1-1.4; Native American descent: HR = 1.3; 95% CI, 1-1.6) and OS (African descent: HR = 1.2; 95% CI, 1.1-1.5; Native American descent, HR, 1.4; 95% CI , 1-1.8).

Native American and African ancestry remained associated with poor prognosis, even after adjusting for biological subtypes and clinical features, the researchers wrote.

Jun J. Yang, PhD

Jun J. Yang

“Although we expected to see some differences in ALL biology by genetic origin, we probably did not expect to see such clear differences across some of these new subtypes (e.g. DUKE4), ”Lee and Yang told Healio.

Implications

The results may simply have scratched the surface of the association of genetic ancestry with ALL results, according to the researchers.

“Our analyzes were on the conservative side and may not have been driven to sufficiently detect differences for the very rare subtypes; therefore, these differences in biology may be much more extensive than we know,” Lee and Yang told Healio.

They said the next steps would include evaluating the genetic lineage association among larger, global ALL cohorts, particularly in Asian and Middle Eastern countries.

“Overall, we would like racial diversity to be put at the center as a consideration in both clinical research and treatment of patients with the goal of eliminating racial gaps in survival,” they said.

In an editorial accompanying the study, Karen R. Rabin, MD, PhD, Director of the Leukemia Program at Texas Children’s Hospital and Associate Professor in the Department of Pediatrics in the Department of Hematology-Oncology at Baylor College of Medicine, wrote that the study “lays a strong foundation for further research,” but highlighted some areas lacking in research.

“Although this study includes a commendable series of international trials and an impressive total number of participants, it nevertheless faces power constraints due to multiple comparisons between the many ALL subtypes and racial and ethnic categories, several of which have relatively small numbers, “Rabin wrote. “Another question that requires further study is how age can interact with genetic lineages. The frequency of ALL subtypes varies considerably with age, and so do patient outcomes. The current study included only a small number of patients aged 18 to 30 years. “

References:

Lee SHR, et al. JAMA Oncol. 2022; doi: 10.1001 / jamaoncol.2021.6826
Rabin KR. JAMA Oncol. 2022; doi: 10.1001 / jamaoncol.2021.6785.

For more information:

Shawn HR Lee, MD, and jun. J. Yang, PhD, can be reached at the Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105; email Lee: shawn.lee@stjude.org; e-mail Yang: jun.yang@stjude.org.

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