Family-based exome-wide association study of childhood acute lymphoblastic leukemia among Hispanics confirms role of ARID5B in susceptibility.

Natalie P Archer,Nalini Ranjit,Maoxiang Qian,Ryan C Zabriskie,Philip J Lupo,Karen R Rabin,Anna V Wilkinson,Jun J Yang,Charnise Goodings,Michael D Swartz,Sharon E Plon,Michael E Scheurer,Ulrik Kristoffer Stoltze ,Federico Antillón‐Klussmann ,Virginia Pérez-Andreu ,Pedro A De Alarcón ,Ting Nien Lin ,Cesar Najera ,Erin C Peckham‐Gregory

doi:10.1371/journal.pone.0180488

Abstract

We conducted an exome-wide association study of childhood acute lymphoblastic leukemia (ALL) among Hispanics to confirm and identify novel variants associated with disease risk in this population. We used a case-parent trio study design; unlike more commonly used case-control studies, this study design is ideal for avoiding issues with population stratification bias among this at-risk ethnic group. Using 710 individuals from 323 Guatemalan and US Hispanic families, two inherited SNPs in ARID5B reached genome-wide level significance: rs10821936, RR = 2.31, 95% CI = 1.70–3.14, p = 1.7×10−8 and rs7089424, RR = 2.22, 95% CI = 1.64–3.01, p = 5.2×10−8. Similar results were observed when restricting our analyses to those with the B-ALL subtype: ARID5B rs10821936 RR = 2.22, 95% CI = 1.63–3.02, p = 9.63×10−8 and ARID5B rs7089424 RR = 2.13, 95% CI = 1.57–2.88, p = 2.81×10−7. Notably, effect sizes observed for rs7089424 and rs10821936 in our study were >20% higher than those reported among non-Hispanic white populations in previous genetic association studies. Our results confirmed the role of ARID5B in childhood ALL susceptibility among Hispanics; however, our assessment did not reveal any strong novel inherited genetic risks for acute lymphoblastic leukemia among this ethnic group.

Highlights

Acute lymphoblastic leukemia (ALL) is the most common malignancy among children, with B-cell ALL (B-ALL) accounting for the majority (80% to 85%) of cases [1,2]
Hispanic children with ALL have a lower 5-year survival rate and a higher incidence of relapse than do non-Hispanic whites [14,15]. These differences in ALL incidence and outcomes among Hispanics could be due to differences in the frequency of known or novel genetic risk factors that are unique to this population
The study cohort consists of a total of 733 individuals from 332 families: 287 families (628 individuals) from Unidad Nacional de Oncologıa Pediatrica (UNOP) in Guatemala, and 45 families (105 individuals) from Texas Children’s Hospital (TCH) in the United States

Summary

Introduction

Acute lymphoblastic leukemia (ALL) is the most common malignancy among children, with B-cell ALL (B-ALL) accounting for the majority (80% to 85%) of cases [1,2]. Genome-wide association studies (GWAS) have identified several inherited genetic variants associated with childhood or adolescent ALL risk, including but not limited to single nucleotide polymorphisms (SNPs) in ARID5B, IKZF1, CEBPE, CDKN2A, PIP4K2A, GATA3, LHPP, and ELK3 [3– 11]. Another important risk factor for childhood ALL is Hispanic ethnicity. Hispanic children with ALL have a lower 5-year survival rate and a higher incidence of relapse than do non-Hispanic whites [14,15] These differences in ALL incidence and outcomes among Hispanics could be due to differences in the frequency of known or novel genetic risk factors that are unique to this population. There is much work remaining to identify the missing heritability of ALL among Hispanics

Methods

Results

Conclusion