Genome-wide association study of childhood B-cell acute lymphoblastic leukemia reveals novel African ancestry-specific susceptibility loci
Abstract
Abstract B-cell acute lymphoblastic leukemia (B-ALL) is the most common pediatric malignancy. Given racial/ethnic differences in incidence and outcomes, B-ALL genome-wide association studies among children of African ancestry are needed. Leveraging multi-institutional datasets with 840 African American children with B-ALL and 3360 controls, nine loci achieved genome-wide significance ( P < 5 × 10 −8 ) after meta-analysis. Two loci were established trans-ancestral susceptibility regions ( IKZF1 , ARID5B ), while the remaining novel loci were specific to African populations. Five-year overall survival among children carrying novel risk alleles was significantly worse (83% versus 96% in non-carriers, P = 4.8 × 10 −3 ). Novel risk variants were also associated with subtype-specific disease ( P < 0.05), including higher susceptibility for a subtype overrepresented in African American children ( TCF3-PBX1 ) and lower susceptibility for a subtype with excellent prognosis ( ETV6-RUNX1 ). Functional experiments revealed novel B-ALL risk variants had allele-specific differences in transcriptional activity ( P < 0.05) in B-cell and leukemia cell lines. These findings shed insights into ancestry-related differences in leukemogenesis and prognosis.
Article Details
Authors (43)
Cindy Im
Andrew R. Raduski
Lauren J. Mills
Kashi Raj Bhattarai
Robert J. Mobley
Kelly R. Barnett
Zhanni Lu
Kenneth Liao
Nathan Anderson
Rebecca A. Johnson
McCourt School of Public Policy
Erica Langer
Anthony J. Hooten
Alix E. Seif
Kathrin M. Bernt
Matthew Tsang
Brandon A. Mamou
Luis Gil-de-Gómez
Julie A. Wolfson
Danielle N. Friedman
Neerav Shukla
Laura J. Klesse
Erin L. Marcotte
Lingyun Ji
Alice Dang
Minjie Luo
Yiming Zhong
Jalen Langie
Charleston W. K. Chiang
Adam de Smith
Joseph L. Wiemels
Andrew DeWan
Xiaomei Ma
Catherine Metayer
Zhaoming Wang
Heather H. Nelson
Nathan Pankratz
Tianzhong Yang
Saonli Basu
Lucie M. Turcotte
Jun J. Yang
Department of Pharmacy and Pharmaceutical Sciences
Daniel Savic
Michael E. Scheurer
Logan G. Spector