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Focused screening of a panel of cancer-related genetic polymorphisms reveals new susceptibility loci for pediatric acute lymphoblastic leukemia

Authors

  • Sonja Offenmüller,

    1. Pediatric Oncology and Hematology, University Children's Hospital, Erlangen, Germany
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  • Yadddanapudi Ravindranath MBBS,

    1. Georgie Ginopolis Chair for Pediatric Cancer and Blood Diseases, Children's Hospital of Michigan and Wayne State University School of Medicine, Detroit, Michigan
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  • Gerard Goyette BS,

    1. Georgie Ginopolis Chair for Pediatric Cancer and Blood Diseases, Children's Hospital of Michigan and Wayne State University School of Medicine, Detroit, Michigan
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  • Deepa Kanakapalli MA,

    1. Georgie Ginopolis Chair for Pediatric Cancer and Blood Diseases, Children's Hospital of Michigan and Wayne State University School of Medicine, Detroit, Michigan
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  • Kathryn S. Miller BSN,

    1. Georgie Ginopolis Chair for Pediatric Cancer and Blood Diseases, Children's Hospital of Michigan and Wayne State University School of Medicine, Detroit, Michigan
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  • Ines B. Brecht MD,

    Corresponding author
    1. Pediatric Oncology and Hematology, University Children's Hospital, Erlangen, Germany
    2. Georgie Ginopolis Chair for Pediatric Cancer and Blood Diseases, Children's Hospital of Michigan and Wayne State University School of Medicine, Detroit, Michigan
    • Correspondence to: Ines B. Brecht, Pediatric Oncology and Hematology, University Children's Hospital, Loschgestrasse 15, Erlangen 91054, Germany.

      E-mail: ines.brecht@uk-erlangen.de

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  • Oliver Zolk MD, PhD

    1. Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
    2. Institute of Pharmacology of Natural Products and Clinical Pharmacology, University of Ulm, Ulm, Germany
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  • Conflict of interest: Nothing to declare.
  • Brecht and Zolk share senior authorship.

Abstract

Background

A genetic predisposition to acute lymphoblastic leukemia (ALL) in childhood is well established. Currently known risk loci, however, explain only one third of the estimated total risk related to common genetic variations.

Procedure

We genotyped 1,421 polymorphisms in 407 candidate genes from the SNP500Cancer database (National Cancer Institute) using the Illumina Cancer SNP Panel. We investigated 78 cases (aged 0–19 years at diagnosis, and mixed ethnic background) of childhood B-precursor ALL and compared genotype data with those of 1,417 HapMap controls. To account for the ethnic diversity of the study population, structured association by genetically matching cases and controls using identity-by-state similarity was used. Case-control association analyses were performed using Cochran–Mantel–Haenszel tests, adjusted for the population substructure.

Results

Common variations rs6966 (3′ UTR of PPP1R13L, chr 19q13.32, P = 4.55 × 10−9) and rs414580 (intron 2 of MSR1, chr 8p22, P = 6.09 × 10−8) were significantly associated with ALL. These SNPs remained significant after adjustment for multiple testing. The SNP rs6966 tags a haplotype block which includes SNPs in PPP1R13L and ERCC2 genes, which are related to DNA repair and cell survival. rs6966 and rs414580 conferred allelic odds ratios of 3.74 (95% confidence interval [CI] 2.31–6.04) and 3.93 (95% CI 2.31–6.69), respectively.

Conclusions

These findings reveal two independent novel susceptibility loci for childhood ALL. Pediatr Blood Cancer 2014; 61:1411–1415. © 2014 Wiley Periodicals, Inc.

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