TY - JOUR
T1 - Novel susceptibility variants at 10p12.31-12.2 for childhood acute lymphoblastic leukemia in ethnically diverse populations
AU - Xu, Heng
AU - Yang, Wenjian
AU - Perez-Andreu, Virginia
AU - Devidas, Meenakshi
AU - Fan, Yiping
AU - Cheng, Cheng
AU - Pei, Deqing
AU - Scheet, Paul
AU - Burchard, Esteban González
AU - Eng, Celeste
AU - Huntsman, Scott
AU - Torgerson, Dara G.
AU - Dean, Michael
AU - Winick, Naomi J.
AU - Martin, Paul L.
AU - Camitta, Bruce M.
AU - Bowman, W. Paul
AU - Willman, Cheryl L.
AU - Carroll, William L.
AU - Mullighan, Charles G.
AU - Bhojwani, Deepa
AU - Hunger, Stephen P.
AU - Pui, Ching Hon
AU - Evans, William E.
AU - Relling, Mary V.
AU - Loh, Mignon L.
AU - Yang, Jun J.
N1 - Funding Information:
Genome-wide genotyping of COG P9904/P9905 samples was performed by the Center for Molecular Medicine with the generous financial support from the Jeffrey Pride Foundation and the National Childhood Cancer Foundation. S.P. Hunger is the Ergen Family Chair in Pediatric Cancer, and J.J. Yang is supported by the American Society of Hematology Scholar Award, Alex Lemonade Stand Foundation for Childhood Cancer Young Investigator Grant, and by the Order of St. Francis Foundation.
Funding Information:
This work was supported by the National Institutes of Health (grant numbers CA156449, CA21765, CA36401, CA98543, CA114766, CA98413, CA140729, and U01GM92666), in part by the Intramural Program of the National Cancer Institute, and by the American Lebanese Syrian Associated Charities (ALSAC).
PY - 2013/5/15
Y1 - 2013/5/15
N2 - Background Acute lymphoblastic leukemia (ALL) is the most common cancer in children and the incidence of ALL varies by ethnicity. Although accumulating evidence indicates inherited predisposition to ALL, the genetic basis of ALL susceptibility in diverse ancestry has not been comprehensively examined. Methods We performed a multiethnic genome-wide association study in 1605 children with ALL and 6661 control subjects after adjusting for population structure, with validation in three replication series of 845 case subjects and 4316 control subjects. Association was tested by two-sided logistic regression. Results 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, African Americans, and Hispanic Americans (P =. 001,. 009, and. 04, respectively). Association was also validated at four known ALL susceptibility loci: ARID5B, IKZF1, CEBPE, and CDKN2A/2B. 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, in parallel with ethnic differences in ALL incidence. Suggestive evidence for modifying effects of age on genetic predisposition to ALL was also observed. ARID5B, IKZF1, CEBPE, and BMI1-PIP4K2A variants cumulatively conferred strong predisposition to ALL, with children carrying six to eight copies of risk alleles at a ninefold (95% confidence interval = 6.9 to 11.8) higher ALL risk relative to those carrying zero to one risk allele at these four single nucleotide polymorphisms. Conclusions 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.
AB - Background Acute lymphoblastic leukemia (ALL) is the most common cancer in children and the incidence of ALL varies by ethnicity. Although accumulating evidence indicates inherited predisposition to ALL, the genetic basis of ALL susceptibility in diverse ancestry has not been comprehensively examined. Methods We performed a multiethnic genome-wide association study in 1605 children with ALL and 6661 control subjects after adjusting for population structure, with validation in three replication series of 845 case subjects and 4316 control subjects. Association was tested by two-sided logistic regression. Results 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, African Americans, and Hispanic Americans (P =. 001,. 009, and. 04, respectively). Association was also validated at four known ALL susceptibility loci: ARID5B, IKZF1, CEBPE, and CDKN2A/2B. 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, in parallel with ethnic differences in ALL incidence. Suggestive evidence for modifying effects of age on genetic predisposition to ALL was also observed. ARID5B, IKZF1, CEBPE, and BMI1-PIP4K2A variants cumulatively conferred strong predisposition to ALL, with children carrying six to eight copies of risk alleles at a ninefold (95% confidence interval = 6.9 to 11.8) higher ALL risk relative to those carrying zero to one risk allele at these four single nucleotide polymorphisms. Conclusions 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.
UR - http://www.scopus.com/inward/record.url?scp=84877969387&partnerID=8YFLogxK
U2 - 10.1093/jnci/djt042
DO - 10.1093/jnci/djt042
M3 - Article
C2 - 23512250
AN - SCOPUS:84877969387
SN - 0027-8874
VL - 105
SP - 733
EP - 742
JO - Journal of the National Cancer Institute
JF - Journal of the National Cancer Institute
IS - 10
ER -