Acute lymphoblastic leukemia (ALL) is the most common cancer in children, and the incidence of the disease varies by ethnicity. Available evidence indicates an inherited predisposition to ALL, but the genetic basis of ALL susceptibility in diverse ancestry has not been examined in detail. Xu and colleagues performed a multiethnic genome-wide association study in 1,605 children with ALL and 6,661 control subjects after adjusting for population structure, with validation performed in three replication series of 845 case subjects and 4,316 control subjects.
A novel ALL susceptibility locus at 10p12.31-12.2 (BMI1-PIP4K2A, rs7088318, P = 1.1×10−11) was identified in the genome-wide association study, with independent replication in European Americans (P = .001), African Americans (P = .009), and Hispanic Americans (P = .04). Association was also validated at four known ALL susceptibility loci: ARID5B, IKZF1, CEBPE, and CDKN2A/2B. The associations at ARID5B, IKZF1, and BMI1-PIP4K2A variants were consistent across ethnicity, with multiple independent signals at IKZF1 and BMI1-PIP4K2A loci.
The frequency of ARID5B and BMI1-PIP4K2A variants differed by ethnicity, paralleling ethnic differences in ALL incidence. Evidence for a modifying effect of age on genetic predisposition to ALL was also observed. The ARID5B, IKZF1, CEBPE, and BMI1-PIP4K2A variants cumulatively conferred strong predisposition to ALL, with children carrying six to eight copies of risk alleles at these single nucleotide polymorphisms being at a ninefold higher ALL risk compared with those carrying 0 to 1 risk alleles.
The investigators concluded, “These findings indicate strong associations between inherited genetic variation and ALL susceptibility in children and shed new light on ALL molecular etiology in diverse ancestry.” ■
Xu H, et al: J Natl Cancer Inst 105:733-742, 2013.