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Certain Childhood ALL Subtypes Linked to Genetic Ancestry

NEW YORK – Genetic ancestry-related differences in tumor subtypes may contribute, in part, to disparities in childhood acute lymphoblastic leukemia outcomes, according to new research by investigators at St. Jude Children's Research Hospital, Singapore's National University Health System, and other centers.

"[A]s we start developing future therapies and protocols for children with ALL, especially with personalized medicine and targeted therapy, we can no longer assume that those that work for white children can also be extrapolated to other non-white populations," senior author Jun Yang, vice chair of the pharmacy and pharmaceutical sciences department and an oncology researcher at St. Jude Children's Research Hospital, explained in an email.

"Our study is the first step to properly characterizing this global diversity, which is needed to inform the design of biologically driven therapeutic protocols," Yang added.

For a study published in JAMA Oncology on Thursday, the researchers used RNA sequencing and other available genomic data to characterize molecular features in tumor samples from more than 2,300 children and young adults with ALL in North America, East Asia, South Asia, and Latin America, who were enrolled in trials done over two decades, between the spring of 2000 and the fall of 2020.

Rather than relying on self-reported ethnicity, the team tapped into sequence data to tease out genetic ancestry patterns in each of the patients, Yang explained, subsequently searching for ties to the molecular tumor subtypes identified.

"[O]ur findings provide a rationale for the development of molecular subtype-driven treatment protocols to help address the racial and ethnic gaps in ALL survival," the authors wrote, though they cautioned that "large-scale pharmacogenomic studies are also needed to identify the exact genomic variation and the mechanisms explaining the racial and ethnic differences in drug response and leukemia molecular subtypes."

Using sequence data for 2,428 childhood or adolescent ALL patients with European, African, Native American, South Asian, or East Asian ancestry who participated in clinical trials in the US, Singapore, Malaysia, or Guatemala, the researchers identified 21 ALL molecular subtypes. Of those, eight showed apparent ties to the patients' genetic ancestry.

In young ALL patients with predominantly East Asian ancestry, the team saw an overrepresentation of tumors containing DUX4 gene alterations and rearrangements involving ZNF384, for example, while patients with Native American ancestry were more prone to tumors with TCF3-PBX1 fusions and rearrangements affecting the CRLF2 gene, as well as lower-than-usual rates of hyperdiploidy and gene fusions involving ETV6 and RUNX1.

Tumors marked by hyperdiploidy and DUX4 rearrangements turned up less frequently in ALL patients with African ancestry, on the other hand. Instead, the researchers found that African ancestry coincided with an overrepresentation of tumors with fusions involving the TCF3 and PBX1 genes.

"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," the authors wrote, noting that "molecular subtype-driven treatment individualization is needed to help address racial and ethnic gaps in outcomes."

But while such approaches could eventually start to narrow the gap in ALL outcomes for children and young adults with ALL, the team's work revealed disparities that went beyond tumor subtype alone. With multivariable regression analyses in a subset of study participants, the group found that African or Native American ancestry coincided with poorer-than-usual event-free survival and overall survival outcomes not explained by tumor subtype differences.

"Granular analysis of individual-level socioeconomic status, access to care, and adherence factors should be explored in future studies and may inform the development of holistic approaches to address racial and ethnic disparities and improve care for all patients," the authors noted.

In a related JAMA Oncology editorial, Karen Rabin, a researcher and physician at Texas Children's Cancer Center, called the study "a much-needed update on the association of genetic ancestry with childhood ALL subtypes and outcomes" that "lays a strong foundation for further investigations in the modern genomic era."

"Although this study focuses on genomic data, the authors acknowledge that non-biological factors may also be associated with racial and ethnic disparities in ALL outcomes," Rabin wrote, noting that the "interplay between genetically defined ancestry and social determinants that affect outcomes is complex."

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