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BMI1 enhancer polymorphism underlies chromosome 10p12.31 association with childhood acute lymphoblastic leukemia.

Publication ,  Journal Article
de Smith, AJ; Walsh, KM; Francis, SS; Zhang, C; Hansen, HM; Smirnov, I; Morimoto, L; Whitehead, TP; Kang, A; Shao, X; Barcellos, LF; Zhang, L ...
Published in: Int J Cancer
December 1, 2018

Genome-wide association studies of childhood acute lymphoblastic leukemia (ALL) have identified regions of association at PIP4K2A and upstream of BMI1 at chromosome 10p12.31-12.2. The contribution of both loci to ALL risk and underlying functional variants remain to be elucidated. We carried out single nucleotide polymorphism (SNP) imputation across chromosome 10p12.31-12.2 in Latino and non-Latino white ALL cases and controls from two independent California childhood leukemia studies, and additional Genetic Epidemiology Research on Aging study controls. Ethnicity-stratified association analyses were performed using logistic regression, with meta-analysis including 3,133 cases (1,949 Latino, 1,184 non-Latino white) and 12,135 controls (8,584 Latino, 3,551 non-Latino white). SNP associations were identified at both BMI1 and PIP4K2A. After adjusting for the lead PIP4K2A SNP, genome-wide significant associations remained at BMI1, and vice-versa (pmeta < 10-10 ), supporting independent effects. Lead SNPs differed by ethnicity at both peaks. We sought functional variants in tight linkage disequilibrium with both the lead Latino SNP among Admixed Americans and lead non-Latino white SNP among Europeans. This pinpointed rs11591377 (pmeta = 2.1 x 10-10 ) upstream of BMI1, residing within a hematopoietic stem cell enhancer of BMI1, and which showed significant preferential binding of the risk allele to MYBL2 (p = 1.73 x 10-5 ) and p300 (p = 1.55 x 10-3 ) transcription factors using binomial tests on ChIP-Seq data from a SNP heterozygote. At PIP4K2A, we identified rs4748812 (pmeta = 1.3 x 10-15 ), which alters a RUNX1 binding motif and demonstrated chromosomal looping to the PIP4K2A promoter. Fine-mapping chromosome 10p12 in a multi-ethnic ALL GWAS confirmed independent associations and identified putative functional variants upstream of BMI1 and at PIP4K2A.

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Published In

Int J Cancer

DOI

EISSN

1097-0215

Publication Date

December 1, 2018

Volume

143

Issue

11

Start / End Page

2647 / 2658

Location

United States

Related Subject Headings

  • Young Adult
  • Trans-Activators
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Polymorphism, Single Nucleotide
  • Polycomb Repressive Complex 1
  • Phosphotransferases (Alcohol Group Acceptor)
  • Oncology & Carcinogenesis
  • Male
  • Logistic Models
  • Linkage Disequilibrium
 

Citation

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de Smith, A. J., Walsh, K. M., Francis, S. S., Zhang, C., Hansen, H. M., Smirnov, I., … Wiemels, J. L. (2018). BMI1 enhancer polymorphism underlies chromosome 10p12.31 association with childhood acute lymphoblastic leukemia. Int J Cancer, 143(11), 2647–2658. https://doi.org/10.1002/ijc.31622
Smith, Adam J. de, Kyle M. Walsh, Stephen S. Francis, Chenan Zhang, Helen M. Hansen, Ivan Smirnov, Libby Morimoto, et al. “BMI1 enhancer polymorphism underlies chromosome 10p12.31 association with childhood acute lymphoblastic leukemia.Int J Cancer 143, no. 11 (December 1, 2018): 2647–58. https://doi.org/10.1002/ijc.31622.
de Smith AJ, Walsh KM, Francis SS, Zhang C, Hansen HM, Smirnov I, et al. BMI1 enhancer polymorphism underlies chromosome 10p12.31 association with childhood acute lymphoblastic leukemia. Int J Cancer. 2018 Dec 1;143(11):2647–58.
de Smith, Adam J., et al. “BMI1 enhancer polymorphism underlies chromosome 10p12.31 association with childhood acute lymphoblastic leukemia.Int J Cancer, vol. 143, no. 11, Dec. 2018, pp. 2647–58. Pubmed, doi:10.1002/ijc.31622.
de Smith AJ, Walsh KM, Francis SS, Zhang C, Hansen HM, Smirnov I, Morimoto L, Whitehead TP, Kang A, Shao X, Barcellos LF, McKean-Cowdin R, Zhang L, Fu C, Wang R, Yu H, Hoh J, Dewan AT, Metayer C, Ma X, Wiemels JL. BMI1 enhancer polymorphism underlies chromosome 10p12.31 association with childhood acute lymphoblastic leukemia. Int J Cancer. 2018 Dec 1;143(11):2647–2658.
Journal cover image

Published In

Int J Cancer

DOI

EISSN

1097-0215

Publication Date

December 1, 2018

Volume

143

Issue

11

Start / End Page

2647 / 2658

Location

United States

Related Subject Headings

  • Young Adult
  • Trans-Activators
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Polymorphism, Single Nucleotide
  • Polycomb Repressive Complex 1
  • Phosphotransferases (Alcohol Group Acceptor)
  • Oncology & Carcinogenesis
  • Male
  • Logistic Models
  • Linkage Disequilibrium