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Multicenter Study
. 2022 Mar 1;8(3):354-363.
doi: 10.1001/jamaoncol.2021.6826.

Association of Genetic Ancestry With the Molecular Subtypes and Prognosis of Childhood Acute Lymphoblastic Leukemia

Shawn H R Lee  1   2   3 , Federico Antillon-Klussmann  4   5 , Deqing Pei  6 , Wenjian Yang  1 , Kathryn G Roberts  7 , Zhenhua Li  3 , Meenakshi Devidas  8   9 , Wentao Yang  1 , Cesar Najera  4 , Hai Peng Lin  10 , Ah Moy Tan  11 , Hany Ariffin  12 , Cheng Cheng  6 , William E Evans  1 , Stephen P Hunger  13 , Sima Jeha  14 , Charles G Mullighan  7 , Mignon L Loh  15 , Allen E J Yeoh  2   3 , Ching-Hon Pui  14 , Jun J Yang  1   14
Affiliations
Multicenter Study

Association of Genetic Ancestry With the Molecular Subtypes and Prognosis of Childhood Acute Lymphoblastic Leukemia

Shawn H R Lee et al. JAMA Oncol. .

Erratum in

  • Error in Figure.
    [No authors listed] [No authors listed] JAMA Oncol. 2022 Mar 1;8(3):484. doi: 10.1001/jamaoncol.2022.0283. JAMA Oncol. 2022. PMID: 35297978 Free PMC article. No abstract available.

Abstract

Importance: Racial and ethnic disparities persist in the incidence and treatment outcomes of childhood acute lymphoblastic leukemia (ALL). However, there is a paucity of data describing the genetic basis of these disparities, especially in association with modern ALL molecular taxonomy and in the context of contemporary treatment regimens.

Objective: To evaluate the association of genetic ancestry with childhood ALL molecular subtypes and outcomes of modern ALL therapy.

Design, setting, and participants: This multinational, multicenter genetic association study was conducted from March 1, 2000, to November 20, 2020, among 2428 children and adolescents with ALL enrolled in frontline trials from the United States, South East Asia (Singapore and Malaysia), and Latin America (Guatemala), representing diverse populations of European, African, Native American, East Asian, and South Asian descent. Statistical analysis was conducted from February 3, 2020, to April 19, 2021.

Main outcomes and measures: Molecular subtypes of ALL and genetic ancestry were comprehensively characterized by performing RNA sequencing. Associations of genetic ancestries with ALL molecular subtypes and treatment outcomes were then evaluated.

Results: Among the participants in the study, 1340 of 2318 (57.8%) were male, and the mean (SD) age was 7.8 (5.3) years. Of 21 ALL subtypes identified, 8 were associated with ancestry. East Asian ancestry was positively associated with the frequency of somatic DUX4 (odds ratio [OR], 1.30 [95% CI, 1.16-1.45]; P < .001) and ZNF384 (OR, 1.40 [95% CI, 1.18-1.66]; P < .001) gene rearrangements and negatively associated with BCR-ABL1-like ALL (OR, 0.79 [95% CI, 0.66-0.92]; P = .002) and T-cell ALL (OR, 0.80 [95% CI, 0.71-0.90]; P < .001). By contrast, occurrence of CRLF2 rearrangements was associated with Native American ancestry (OR, 1.48 [95% CI, 1.29-1.69]; P < .001). When the percentage of Native American ancestry increased, ETV6-RUNX1 fusion became less frequent (OR, 0.80 [95% CI, 0.70-0.91]; P < .001), with the opposite trend observed for ETV6-RUNX1-like ALL. There was a marked preponderance of T-cell ALL in children of African descent compared with those with a high percentage of Native American ancestry (African: OR, 1.22 [95% CI, 1.07-1.37]; P = .003; Native American: OR, 0.53 [95% CI, 0.40-0.67]; P < .001). African ancestry was also positively associated with the prevalence of TCF3-PBX1 (OR, 1.49 [95% CI, 1.25-1.76]; P < .001) and negatively associated with DUX4 rearrangements (OR, 0.70 [95% CI, 0.48-0.93]; P = .01) and hyperdiploidy (OR, 0.77 [95% CI, 0.68-0.86]; P < .001). African and Native American ancestries as continuous variables were both associated with poorer event-free survival (for every 25% increase in ancestry: hazard ratio [HR], 1.2; 95% CI, 1.1-1.4; P = .001 for African ancestry; HR, 1.3; 95% CI, 1.0-1.6; P = .04 for Native American ancestry) and overall survival (for every 25% increase in ancestry: HR, 1.2; 95% CI, 1.1-1.5; P = .01 for African ancestry; HR, 1.4; 95% CI, 1.0-1.8; P = .03 for Native American ancestry). Even after adjusting for biological subtypes and clinical features, Native American and African ancestries remained associated with poor prognosis.

Conclusions and relevance: 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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Cheng reported receiving grants from the National Institutes of Health (NIH) Cancer Center during the conduct of the study. Dr Evans reported serving as a member of the Scientific Advisory Board for Princess Maxima Centre for Child Oncology and serving as a board member for BioSkryb Inc outside the submitted work. Dr Hunger reported holding common stock for Amgen; receiving personal fees from Amgen, Novartis, and Jazz outside the submitted work. Dr Mullighan reported receiving grants from Pfizer and AbbVie; and personal fees from Amgen and Illumina outside the submitted work. Dr Loh reported receiving personal fees from Medisix Therapeutics outside the submitted work. Dr Yeoh reported receiving grants from National Medical Research Council Singapore during the conduct of the study; and personal fees from Amgen South East Asia outside the submitted work. Dr Pui reported receiving grants from the National Cancer Institute during the conduct of the study; and receiving salary support from the American Lebanese Syrian Associated Charities outside the submitted work. Dr J. J. Yang reported receiving grants from the NIH during the conduct of the study; and grants from the NIH outside the submitted work; and having a patent pending for Methods for Determining Benefit of Chemotherapy. No other disclosures were reported.

Figures

Figure.
Figure.. Kaplan-Meier Survival Curves Comparing All 7 Genetically Defined Racial and Ethnic Categories for 1596 Children, Adolescents, and Young Adults With Acute Lymphoblastic Leukemia
Criteria for defining racial and ethnic categories are as described in the eMethods in the Supplement. Event-free survival (A), overall survival (B), and cumulative incidence of any relapse (C) were worse for Hispanic and Black patients, with South Asian patients having the most favorable outcomes. P values were obtained after adjusting for treatment protocol.
See this image and copyright information in PMC

Comment in

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