Study Finds ALL Genetic Variant That Indicates Why Hispanic, Pediatric Patients Are Likely to Develop Disease

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According to a study by the Keck School of Medicine of University of Southern California (USC), a key genetic variant that contributes toward the increased risk of acute lymphoblastic leukemia (ALL) in children has been detected. Compared with non-Hispanic White children, the disease is about 30% to 40% more likely to affect children of Hispanic or Latino origin.¹

For this study, the investigators used a statistical method that allowed the disentangling of genetic variants in a region of the genome, and a variant was found at a high frequency in pediatric patients of Hispanic or Latino origin that increased the risk of ALL onset by approximately 1.4 times. In addition, the researchers performed further tests to better understand the variant—which is located on the IKZF1 gene—that underlies B-cell development and relates to ALL through its influence of B-cell development.¹

“Together, the analyses in our study provide the statistical, biological, and evolutionary insights behind this increased risk, and may ultimately aid scientists working to develop screening tools and therapies for ALL,” said study co-author Charleston Chiang, PhD, associate professor of population and public health sciences and associate director of the Center of Genetic Epidemiology at the Keck School of Medicine, in a press release.¹

For this study, investigators evaluated children of Hispanic or Latino background with and without ALL (ALL cases: n = 1878; controls: n = 8441), children of non-Hispanic White background (ALL cases: n = 1162; controls: n = 57341) and children of East Asian background (ALL cases: n = 318; controls: n = 5017). The researchers specifically focused on the IKZF1 gene, which was previously known to be linked to ALL but not necessarily with ethnic risk disparities. Researchers investigated each position along the gene—the single nucleotide polymorphism (SNP)—to determine whether or not having a certain variant increased the risk of developing ALL.²

The investigators determined that there was an association with the established risk gene IKZF1 with an increased risk of ALL in Hispanic and Latino pediatric patients compared with non-Hispanic White patients (OR = 1.44, 95% confidence interval = 1.33–1.55), as well as the relatively high RAF (18%) in Hispanic and Latino populations but its absence (< 0.5%) in European populations.²

Further, 3 independent SNPs were associated with a high ALL incidence in patients, of which 1 was present in approximately 30% of patients of Hispanic or Latino origin in the US and less than 1% of people of European origin. In addition, the investigators note that though risk for ALL may be low across all groups, children who had the variant—located at SNP rs76880433—were approximately 1.44 times as likely to develop ALL compared with children who do not have the variant.¹

“Looking at all of this together, we think that the risk variant is reducing IKZF1 expression,” de Smith said in the press release. “By doing so, it’s keeping B-cells in a more immature state, which would increase ALL risk by giving the cells more chance to develop mutations that could eventually lead to overt leukemia.”¹

According to the investigators, these findings can serve as a valuable resource in the development of effective screening tools that can predict who may develop ALL; however, they note that more research is needed. In addition, the findings also show potential ways of treating ALL (eg, progressing B-cell development after it stalls). Additional research will continue to explore the associations between the gene variant and adolescents and young adults of Hispanic and Latino descent.¹

“Combined with the fact that around 30% of Hispanic/Latino people in the US carry this gene variant, but it’s basically absent in people of predominantly European ancestry, we think it's an important contributor to the increased ALL risk among this group,” said the study’s lead author Adam de Smith, PhD, an assistant professor of population and public health sciences and a member of the USC Norris Comprehensive Cancer Center at the Keck School of Medicine, and scholar of the Leukemia & Lymphoma Society, in the press release. “We also need to understand whether this variant is associated with different patient outcomes, such as the risk of relapse or chances of survival, and why that might be.”¹

References

1. Keck School of Medicine of USC. USC researchers find genetic variant contributing to disparities in childhood leukemia risk. News release. March 26, 2024. Accessed March 29, 2024. https://www.eurekalert.org/news-releases/1039019

2. de Smith, A, Wahlster, L, Jeon, S, et al. A noncoding regulatory variant in IKZF1 increases acute lymphoblastic leukemia risk in Hispanic/Latino children. Cell Genomics. 2024. March 26, 2024. doi:10.1016/j.xgen.2024.100526.