Impact of Genetic Ancestry on Genomics and Survival Outcomes in T-cell Acute Lymphoblastic Leukemia

Newman H, Lee SHR, Pölönen P, Shraim R, Li Y, Liu H, Aplenc R, Bandyopadhyay S, Chen C, Devidas M, Diorio C, Dunsmore K, Elghawy O, Elhachimi A, Fuller T, Gupta S, Hall J, Hughes AD, Hunger SP, Loh ML, Martinez Z, McCoy MF, Mullen CG, Pounds SB, Raetz E, Seffernick AE, Shi G, Sussman J, Tan K, Uppuluri L, Vincent TL, Wang’ondu R, Winestone LE, Winter SS, Wood BL, Wu G, Xu J, Yang W, Mullighan CG, Yang JJ, Bona K, Teachey DT. Impact of Genetic Ancestry on Genomics and Survival Outcomes in T-cell Acute Lymphoblastic Leukemia. Blood Cancer Discov. 2025 Sep 1;6(5):412-424. doi: 10.1158/2643-3230.BCD-25-0049. Epub 2025 May 28. PMID: 40434808; PMCID: PMC12405861.

The influence of genetic ancestry on genomics in T-cell acute lymphoblastic leukemia (T-ALL) has not been fully explored. We examined the impact of genetic ancestry on multiomic alterations, survival outcomes, and risk stratification. Among 1,309 children and young adults with T-ALL treated on the Children’s Oncology Group trial AALL0434, the prognostic value of five commonly altered T-ALL genes varied by ancestry—including NOTCH1, which was associated with superior overall survival for patients of European ancestry but was nonprognostic among patients of African ancestry. Integrating genetic ancestry with published T-ALL risk classifiers, we identified that an X01 penalized Cox regression classifier stratified patients regardless of ancestry, whereas a European multigene classifier misclassified patients of certain ancestries. Overall, 80% of patients harbored a genomic alteration in at least one gene with differential prognostic impact in an ancestry-specific manner. These data demonstrate the importance of incorporating genetic ancestry into genomic risk classification.