Scientists at St. Jude Children’s Research Hospital are studying the impact of genetic ancestry on childhood acute lymphoblastic leukemia (ALL). The scientists assembled an international cohort to determine how genetic ancestry affects leukemia biology and outcomes for modern therapy; they found that ancestry itself is an independent factor contributing to differences in treatment outcomes. The findings were published by Lee et al in JAMA Oncology.
Study Background and Methodology
Racial disparities exist in both incidence and treatment outcomes for childhood ALL, and there are limited data on the genetic basis for such disparities. This is further exacerbated by the lack of genomic research in ALL populations from Africa, Latin America, and Asia, even though these populations make up the bulk of pediatric cancer cases globally.
To address these shortcomings, researchers created a diverse cohort of 2,428 children and adolescents with ALL treated on front-line clinical trials. The group was drawn from North America, Southeast Asia, and Latin America, and included individuals of European, African, Native American, East Asian, and South Asian descent.
The researchers used RNA sequencing to comprehensively characterize the ALL molecular subtype and genetic ancestry of each child. The results were analyzed for their associations with clinical features and treatment outcomes.
We need to stop assuming we can develop therapies focusing on White children and then they can just be extrapolated to others. The world is becoming increasingly diverse, and so are children with cancer. As we look to the next generation of therapies for ALL, it’s going to be essential that we consider the diversity of this cancer on a global scale.— Jun J. Yang, PhD
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“As a field, we really need to put diversity front and center in our research going forward,” said corresponding study author Jun J. Yang, PhD, of the St. Jude Department of Pharmacy and Pharmaceutical Sciences and Department of Oncology. “We need to stop assuming we can develop therapies focusing on White children and then they can just be extrapolated to others. The world is becoming increasingly diverse, and so are children with cancer. As we look to the next generation of therapies for ALL, it’s going to be essential that we consider the diversity of this cancer on a global scale.”
The work underscores the importance of biology-driven treatment individualization, which may play a future role in helping to eliminate disparities in ALL outcomes.
Genetic Findings
The researchers found that of 21 known ALL subtypes, 8 were associated with ancestry. East Asian ancestry was positively associated with subtypes with a good prognosis (such as DUX4 rearrangements) and negatively associated with those with a poor prognosis (including BCR-ABL1–like ALL and T-cell ALL).
On the contrary, Native American ancestry was linked to CRLF2 rearrangements, which mark particularly aggressive ALL cases. Children with African ancestry showed the highest incidence of T-cell ALL cases—sevenfold higher than those of Native American descent (eg, certain Hispanic groups). African and Native American ancestries were both associated with lower event-free survival and overall survival than other groups.
“In terms of ALL biology, there are actually a lot of differences across ancestries which have an impact on survival and treatment outcomes,” said first author Shawn Lee, MD, of the St. Jude Department of Pharmaceutical Sciences. “With this information, we can help individualize treatment according to biology and even consider risk stratification according to ancestry to assist in planning biology-driven treatment protocols.”
In terms of ALL biology, there are actually a lot of differences across ancestries which have an impact on survival and treatment outcomes.... With this information, we can help individualize treatment according to biology and even consider risk stratification according to ancestry to assist in planning biology-driven treatment protocols.— Shawn Lee, MD
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A More Complete Picture of ALL Genetics
The majority of the research that led to current treatments for ALL was conducted in the United States and Europe. Thus, clinical and genomic data on children of diverse ancestral descent are limited. This study complements prior research from the Yang laboratory, which discovered how genetic variation in NUTD15 explains the excessive risk for thiopurine-related toxicity in Asian children with ALL. These NUDT15 variants are rarely found in children with European ancestry, highlighting how important findings can be missed if studies do not include diversity in genetic ancestry.
The research also underscores the need for greater granularity in how genetic ancestry is considered. For example, Asian ancestry includes South Asians, East Asians, and Southeast Asians, which are genetically distinct populations, with notable differences in ALL tumor biology and treatment outcomes.
The study authors concluded, “This study suggests that ALL molecular subtypes and prognosis are associated with genetic ancestry, potentially pointing to a genetic basis for some of the racial and ethnic disparities in ALL. Therefore, molecular subtype–driven treatment individualization is needed to help address racial and ethnic gaps in outcomes.”
Disclosure: The study was funded by the National Institutes of Health, Singapore National Medical Research Council Clinician Research Training Fellowship and Clinician-Scientist Investigator Awards, and ALSAC. For full disclosures of the study authors, visit jamanetwork.com.
