Genetic ancestry provides important context for understanding global diversity in childhood leukemia

Racial disparities exist in both the incidence and treatment outcomes of childhood ALL, and there is little data on the genetic basis of these disparities. This is further exacerbated by the lack of genomic research in ALL populations of Africa, Latin America and Asiaeven though these populations constitute the bulk of pediatric cancer cases worldwide.

To address this issue, the researchers created a diverse cohort of 2,428 children and adolescents with ALL treated in frontline clinical trials. The group was from North America, South East Asia and Latin America and included people of European, African, Native American, East Asian, and South Asian ancestry.

The researchers used a genomic technique called RNA sequencing to comprehensively characterize ALL molecular subtypes and each child’s genetic ancestry. The results were analyzed for their associations with clinical characteristics and treatment outcomes.

“As a field, we really need to put diversity at the center of our research going forward,” said the corresponding author. Jun J. Yang, Ph.D., St. Jude Department of Pharmacy and Pharmaceutical Sciences and Department of Oncology. “We need to stop assuming that we can develop therapies that are focused on white children and then can just be extrapolated to others. The world is becoming more and more diverse, and so are children with cancer. we look to the next generation of therapies for ALL, it is going to be essential to consider the diversity of this cancer on a global scale.”

Genetic discoveries

The work underscores the importance of biology-driven individualization of treatment, which may play a future role in helping to eliminate disparities in ALL outcomes.

The researchers found that of 21 known ALL subtypes, eight were associated with ancestry. East Asian ancestry was positively associated with subtypes with good prognosis such as DUX4 rearrangements and negatively associated with those with a poor prognosis, including BCR-ABL1-like ALL and T-ALL.

Rather, Native American ancestry was tied to CRLF2 rearrangements, which mark ALL particularly aggressive cases. Children of African descent showed the highest incidence of T-ALL cases, seven times higher than those of Native American descent (eg, some Hispanic groups). Both African and Native American ancestries were associated with lower event-free survival and lower overall survival than other groups.

“In terms of ALL biology, there are actually many differences between ancestors that impact survival and treatment outcomes,” said first author Shawn Lee, MD, St. Jude Department of Pharmaceutical Sciences. “With this information, we can help individualize treatment based on biology and even consider risk stratification based on ancestry to help plan biology-based treatment protocols.”

A more complete picture of ALL genetics

Much of the research that has led to current treatments for ALL has been conducted in United States and Europe. Thus, clinical and genomic data on children of various ancestral origins are limited. This study complements previous Yang lab research that uncovered how genetic variation in NUTD15 explains the excessive risk of thiopurine toxicity in Asian children with ALL. Those NUDT15 variants are rarely found in children of European ancestry, highlighting how important findings can be missed if studies do not include diversity in genetic ancestry.

The research also highlights the need for greater granularity in how genetic ancestry is taken into account. 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. .

“Appropriate research that includes children from all walks of life and from all parts of the world is important to help us better understand the diversity of patients diagnosed with ALL and other cancers,” said Carlos Rodriguez Galindo, MD, Director of St. Jude Global. “We recognize and appreciate the need for more international cohorts that include children from all parts of the world.”

Authors and funding

The other authors of the study are Federico Antillon and Caesar NajeraNational Pediatric Oncology Unit (Guatemala); Allen EJ Yeoh, Khoo Teck Puat-National University Medical Institute for Children and Yong Loo Lin School of Medicine (Singapore); Hai Peng LinSime Darby Subang Jaya Medical Center (Malaysia); Ah Moy Tan, KK Women’s and Children’s Hospital (Singapore); Hany Ariffin, University of Malaya Medical Center (Malaysia); Stephen HungerChildren’s Hospital philadelphia cream and the University of Pennsylvania; Cute LohBenioff Children’s Hospital and University of California, San Francisco; and Deqing Pei, Wenjian Yang, Catherine Roberts, Zhenhua Li, Meenakshi Devidas, Wentao YangCheng Cheng, William Evans, Sima JehaCharles Mulligan and Ching Hon Puiall from St. Jude.

The study was funded by the National Institutes of Health (CA21765, CA98543, CA114766, CA98413, CA180886, CA180899, GM92666, GM115279, CA234490 and GM097119), Singapore National Medical Research Council Clinician Research Training Fellowship and Clinician-Scientist Investigator Awards and ALSAC. , the fundraising and outreach organization of St. Jude.

St. Jude Children’s Research Hospital

St. Jude Children’s Research Hospital is at the forefront of how the world understands, treats, and cures childhood cancer and other life-threatening illnesses. It is the only comprehensive cancer center designated by the National Cancer Institute devoted solely to children. Treatments developed at St. Jude have helped increase the overall childhood cancer survival rate from 20% to 80% since the hospital opened more than 50 years ago. St. Jude freely shares the breakthroughs it achieves, and every child saved at St. Jude means doctors and scientists around the world can use that knowledge to save thousands more children. To learn more, visit stjude.org or follow St. Jude on social media at @stjuderesearch.

SOURCE St. Jude Children’s Research Hospital

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