Shawn H R Lee1,2,3, Federico Antillon-Klussmann4,5, Deqing Pei6, Wenjian Yang1, Kathryn G Roberts7, Zhenhua Li3, Meenakshi Devidas8,9, Wentao Yang1, Cesar Najera4, Hai Peng Lin10, Ah Moy Tan11, Hany Ariffin12, Cheng Cheng6, William E Evans1, Stephen P Hunger13, Sima Jeha14, Charles G Mullighan7, Mignon L Loh15, Allen E J Yeoh2,3, Ching-Hon Pui14, Jun J Yang1,14. 1. Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, Tennessee. 2. Khoo Teck Puat-National University Children's Medical Institute, National University Hospital, National University Health System, Singapore, Singapore. 3. Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. 4. National Pediatric Oncology Unit, Guatemala City, Guatemala. 5. School of Medicine, Francisco Marroquin University, Guatemala City, Guatemala. 6. Department of Biostatistics, St Jude Children's Research Hospital, Memphis, Tennessee. 7. Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee. 8. Department of Global Pediatric Medicine, St Jude Children's Research Hospital, Memphis, Tennessee. 9. Department of Biostatistics, University of Florida, Gainesville. 10. Department of Paediatrics, Sime Darby Medical Centre Subang Jaya, Subang Jaya, Malaysia. 11. Department of Paediatrics, KK Women's and Children's Hospital, Singapore, Singapore. 12. Department of Paediatrics, University of Malaya Medical Centre, Kuala Lumpur, Malaysia. 13. Department of Pediatrics and Center for Childhood Cancer Research, Children's Hospital of Philadelphia and the Perelman School of Medicine at The University of Pennsylvania, Philadelphia. 14. Department of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee. 15. Department of Pediatrics, Benioff Children's Hospital and the Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco.
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.
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.
Authors: Minerva Mata-Rocha; Angelica Rangel-López; Elva Jimenez-Hernandez; Juan Carlos Nuñez-Enríquez; Blanca Angélica Morales-Castillo; Norberto Sánchez-Escobar; Omar Alejandro Sepúlveda-Robles; Juan Carlos Bravata-Alcántara; Alan Steve Nájera-Cortés; María Luisa Pérez-Saldivar; Janet Flores-Lujano; David Aldebarán Duarte-Rodríguez; Norma Angélica Oviedo de Anda; Maria de Los Angeles Romero Tlalolini; Carmen Alaez Verson; Jorge Alfonso Martín-Trejo; Jose Esteban Muñoz Medina; Cesar Raul Gonzalez-Bonilla; Maria de Los Angeles Hernandez Cueto; V C Bekker-Méndez; Silvia Jiménez-Morales; Aurora Medina-Sansón; Raquel Amador-Sánchez; José Gabriel Peñaloza-González; José Refugio Torres-Nava; Rosa Martha Espinosa-Elizondo; Beatriz Cortés-Herrera; Luz Victoria Flores-Villegas; Laura Elizabeth Merino-Pasaye; Maria de Lourdes Gutierrez-Rivera; Martha Margarita Velazquez-Aviña; Jessica Denisse Santillan-Juarez; Alma Gurrola-Silva; Gabriela Alicia Hernández Echáurregui; Alfredo Hidalgo-Miranda; José Arellano Galindo; Haydeé Rosas-Vargas; Juan Manuel Mejía-Aranguré Journal: Front Pediatr Date: 2022-05-24 Impact factor: 3.569
Authors: Janet Flores-Lujano; David Aldebarán Duarte-Rodríguez; Elva Jiménez-Hernández; Jorge Alfonso Martín-Trejo; Aldo Allende-López; José Gabriel Peñaloza-González; María Luisa Pérez-Saldivar; Aurora Medina-Sanson; José Refugio Torres-Nava; Karina Anastacia Solís-Labastida; Luz Victoria Flores-Villegas; Rosa Martha Espinosa-Elizondo; Raquel Amador-Sánchez; Martha Margarita Velázquez-Aviña; Laura Elizabeth Merino-Pasaye; Nora Nancy Núñez-Villegas; Ana Itamar González-Ávila; María de Los Ángeles Del Campo-Martínez; Martha Alvarado-Ibarra; Vilma Carolina Bekker-Méndez; Rocío Cárdenas-Cardos; Silvia Jiménez-Morales; Roberto Rivera-Luna; Haydee Rosas-Vargas; Norma C López-Santiago; Angélica Rangel-López; Alfredo Hidalgo-Miranda; Elizabeth Vega; Minerva Mata-Rocha; Omar Alejandro Sepúlveda-Robles; José Arellano-Galindo; Juan Carlos Núñez-Enríquez; Juan Manuel Mejía-Aranguré Journal: Front Public Health Date: 2022-09-14