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|Title:||Novel susceptibility variants at 10p12.31-12.2 for childhood acute lymphoblastic leukemia in ethnically diverse populations|
|Citation:||Journal of the National Cancer Institute, 2013; 105(10):733-742|
|Publisher:||Oxford University Press|
|Heng Xu, Wenjian Yang, Virginia Perez-Andreu, Meenakshi Devidas, Yiping Fan, Cheng Cheng, Deqing Pei, Paul Scheet, Esteban González Burchard, Celeste Eng, Scott Huntsman, Dara G. Torgerson, Michael Dean, Naomi J. Winick, Paul L. Martin, Bruce M. Camitta, W. Paul Bowman, Cheryl L. Willman, William L. Carroll, Charles G. Mullighan, Deepa Bhojwani, Stephen P. Hunger, Ching-Hon Pui, William E. Evans, Mary V. Relling, Mignon L. Loh, Jun J. Yang|
|Abstract:||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.|
|Keywords:||Alleles; acute lymphocytic leukemia; cancer; child; ethnic group; genes; p16; genetic predisposition to disease; genotype; hispanics or latinos; leukemia; lymphocytic; acute; childhood; single nucleotide polymorphism; protein p16; genetics; African American; genome-wide association study; causality; ethnic differences|
|Rights:||© The Author 2013. Published by Oxford University Press. All rights reserved.|
|Appears in Collections:||Aurora harvest 3|
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