Novel susceptibility variants at 10p12.31-12.2 for childhood acute lymphoblastic leukemia in ethnically diverse populations

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. MullighanDeepa Bhojwani, Stephen P. Hunger, Ching Hon Pui, William E. Evans, Mary V. Relling, Mignon L. Loh, Jun J. Yang

Research output: Contribution to journalArticle

122 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)733-742
Number of pages10
JournalJournal of the National Cancer Institute
Volume105
Issue number10
DOIs
StatePublished - May 15 2013

Fingerprint

Precursor Cell Lymphoblastic Leukemia-Lymphoma
Population
Genome-Wide Association Study
Alleles
Incidence
Genetic Predisposition to Disease
Hispanic Americans
African Americans
Single Nucleotide Polymorphism
Logistic Models
Confidence Intervals

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Novel susceptibility variants at 10p12.31-12.2 for childhood acute lymphoblastic leukemia in ethnically diverse populations. / Xu, Heng; Yang, Wenjian; Perez-Andreu, Virginia; Devidas, Meenakshi; Fan, Yiping; Cheng, Cheng; Pei, Deqing; Scheet, Paul; Burchard, Esteban González; Eng, Celeste; Huntsman, Scott; Torgerson, Dara G.; Dean, Michael; Winick, Naomi J.; Martin, Paul L.; Camitta, Bruce M.; Bowman, W. Paul; Willman, Cheryl L.; Carroll, William L.; Mullighan, Charles G.; Bhojwani, Deepa; Hunger, Stephen P.; Pui, Ching Hon; Evans, William E.; Relling, Mary V.; Loh, Mignon L.; Yang, Jun J.

In: Journal of the National Cancer Institute, Vol. 105, No. 10, 15.05.2013, p. 733-742.

Research output: Contribution to journalArticle

Xu, H, Yang, W, Perez-Andreu, V, Devidas, M, Fan, Y, Cheng, C, Pei, D, Scheet, P, Burchard, EG, Eng, C, Huntsman, S, Torgerson, DG, Dean, M, Winick, NJ, Martin, PL, Camitta, BM, Bowman, WP, Willman, CL, Carroll, WL, Mullighan, CG, Bhojwani, D, Hunger, SP, Pui, CH, Evans, WE, Relling, MV, Loh, ML & Yang, JJ 2013, 'Novel susceptibility variants at 10p12.31-12.2 for childhood acute lymphoblastic leukemia in ethnically diverse populations', Journal of the National Cancer Institute, vol. 105, no. 10, pp. 733-742. https://doi.org/10.1093/jnci/djt042
Xu, Heng ; Yang, Wenjian ; Perez-Andreu, Virginia ; Devidas, Meenakshi ; Fan, Yiping ; Cheng, Cheng ; Pei, Deqing ; Scheet, Paul ; Burchard, Esteban González ; Eng, Celeste ; Huntsman, Scott ; Torgerson, Dara G. ; Dean, Michael ; Winick, Naomi J. ; Martin, Paul L. ; Camitta, Bruce M. ; Bowman, W. Paul ; Willman, Cheryl L. ; Carroll, William L. ; Mullighan, Charles G. ; Bhojwani, Deepa ; Hunger, Stephen P. ; Pui, Ching Hon ; Evans, William E. ; Relling, Mary V. ; Loh, Mignon L. ; Yang, Jun J. / Novel susceptibility variants at 10p12.31-12.2 for childhood acute lymphoblastic leukemia in ethnically diverse populations. In: Journal of the National Cancer Institute. 2013 ; Vol. 105, No. 10. pp. 733-742.
@article{ca486cf2ffbf42c4bf6d9fbd90bb7266,
title = "Novel susceptibility variants at 10p12.31-12.2 for childhood acute lymphoblastic leukemia in ethnically diverse populations",
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.",
author = "Heng Xu and Wenjian Yang and Virginia Perez-Andreu and Meenakshi Devidas and Yiping Fan and Cheng Cheng and Deqing Pei and Paul Scheet and Burchard, {Esteban Gonz{\'a}lez} and Celeste Eng and Scott Huntsman and Torgerson, {Dara G.} and Michael Dean and Winick, {Naomi J.} and Martin, {Paul L.} and Camitta, {Bruce M.} and Bowman, {W. Paul} and Willman, {Cheryl L.} and Carroll, {William L.} and Mullighan, {Charles G.} and Deepa Bhojwani and Hunger, {Stephen P.} and Pui, {Ching Hon} and Evans, {William E.} and Relling, {Mary V.} and Loh, {Mignon L.} and Yang, {Jun J.}",
year = "2013",
month = "5",
day = "15",
doi = "10.1093/jnci/djt042",
language = "English (US)",
volume = "105",
pages = "733--742",
journal = "Journal of the National Cancer Institute",
issn = "0027-8874",
publisher = "Oxford University Press",
number = "10",

}

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.

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

UR - http://www.scopus.com/inward/citedby.url?scp=84877969387&partnerID=8YFLogxK

U2 - 10.1093/jnci/djt042

DO - 10.1093/jnci/djt042

M3 - Article

C2 - 23512250

AN - SCOPUS:84877969387

VL - 105

SP - 733

EP - 742

JO - Journal of the National Cancer Institute

JF - Journal of the National Cancer Institute

SN - 0027-8874

IS - 10

ER -