title: Focused screening of a panel of cancer-related genetic polymorphisms reveals new susceptibility loci for pediatric acute lymphoblastic leukemia.
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.
  
  
  METHODS
  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.
authors.affiliation: Pediatric Oncology and Hematology, University Children's Hospital, Erlangen, Germany.
authors.forename: Sonja
authors.initials: S
authors.lastname: Offenmüller
authors.forename: Yadddanapudi
authors.initials: Y
authors.lastname: Ravindranath
authors.forename: Gerard
authors.initials: G
authors.lastname: Goyette
authors.forename: Deepa
authors.initials: D
authors.lastname: Kanakapalli
authors.forename: Kathryn S
authors.initials: KS
authors.lastname: Miller
authors.forename: Ines B
authors.initials: IB
authors.lastname: Brecht
authors.forename: Oliver
authors.initials: O
authors.lastname: Zolk
mesh_terms: D020413:3' Untranslated Regions; D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D005260:Female; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D006801:Humans; D007438:Introns; D008297:Male; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D012189:Retrospective Studies
chemical_list: D020413:3' Untranslated Regions
keywords: ERCC2; MSR1; PPP1R13L; candidate gene association study; childhood acute lymphoblastic leukemia