title: Variation at 10p12.2 and 10p14 influences risk of childhood B-cell acute lymphoblastic leukemia and phenotype.
abstract: Acute lymphoblastic leukemia (ALL) is the major pediatric cancer diagnosed in economically developed countries with B-cell precursor (BCP)-ALL, accounting for approximately 70% of ALL. Recent genome-wide association studies (GWAS) have provided the first unambiguous evidence for common inherited susceptibility to BCP-ALL, identifying susceptibility loci at 7p12.2, 9p21.3, 10q21.2, and 14q11.2. To identify additional BCP-ALL susceptibility loci, we conducted a GWAS and performed a meta-analysis with a published GWAS totaling 1658 cases and 4723 controls, with validation in 1449 cases and 1488 controls. Combined analysis identified novel loci mapping to 10p12.2 (rs10828317, odds ratio [OR] = 1.23; P = 2.30 × 10(-9)) and 10p14 marked by rs3824662 (OR = 1.31; P = 8.62 × 10(-12)). The single nucleotide polymorphism rs10828317 is responsible for the N215S polymorphism in exon 7 of PIP4K2A, and rs3824662 localizes to intron 3 of the transcription factor and putative tumor suppressor gene GATA3. The rs10828317 association was shown to be specifically associated with hyperdiploid ALL, whereas the rs3824662-associated risk was confined to nonhyperdiploid non-TEL-AML1 + ALL. The risk allele of rs3824662 was correlated with older age at diagnosis (P < .001) and significantly worse event-free survivorship (P < .0001). These findings provide further insights into the genetic and biological basis of inherited genetic susceptibility to BCP-ALL and the influence of constitutional genotype on disease development.
authors.affiliation: Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, Surrey, United Kingdom;
authors.forename: Gabriele
authors.initials: G
authors.lastname: Migliorini
authors.forename: Bettina
authors.initials: B
authors.lastname: Fiege
authors.forename: Fay J
authors.initials: FJ
authors.lastname: Hosking
authors.forename: Yussanne
authors.initials: Y
authors.lastname: Ma
authors.forename: Rajiv
authors.initials: R
authors.lastname: Kumar
authors.forename: Amy L
authors.initials: AL
authors.lastname: Sherborne
authors.forename: Miguel Inacio
authors.initials: MI
authors.lastname: da Silva Filho
authors.forename: Jayaram
authors.initials: J
authors.lastname: Vijayakrishnan
authors.forename: Rolf
authors.initials: R
authors.lastname: Koehler
authors.forename: Hauke
authors.initials: H
authors.lastname: Thomsen
authors.forename: Julie A
authors.initials: JA
authors.lastname: Irving
authors.forename: James M
authors.initials: JM
authors.lastname: Allan
authors.forename: Tracy
authors.initials: T
authors.lastname: Lightfoot
authors.forename: Eve
authors.initials: E
authors.lastname: Roman
authors.forename: Sally E
authors.initials: SE
authors.lastname: Kinsey
authors.forename: Eamonn
authors.initials: E
authors.lastname: Sheridan
authors.forename: Pamela
authors.initials: P
authors.lastname: Thompson
authors.forename: Per
authors.initials: P
authors.lastname: Hoffmann
authors.forename: Markus M
authors.initials: MM
authors.lastname: Nöthen
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Mühleisen
authors.forename: Lewin
authors.initials: L
authors.lastname: Eisele
authors.forename: Martin
authors.initials: M
authors.lastname: Zimmermann
authors.forename: Claus R
authors.initials: CR
authors.lastname: Bartram
authors.forename: Martin
authors.initials: M
authors.lastname: Schrappe
authors.forename: Mel
authors.initials: M
authors.lastname: Greaves
authors.forename: Martin
authors.initials: M
authors.lastname: Stanulla
authors.forename: Kari
authors.initials: K
authors.lastname: Hemminki
authors.forename: Richard S
authors.initials: RS
authors.lastname: Houlston
mesh_terms: D000367:Age Factors; D000483:Alleles; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D002648:Child; D002879:Chromosomes, Human, Pair 10; D005091:Exons; D005260:Female; D050990:GATA3 Transcription Factor / Q000235:genetics*; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D007438:Introns; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D016019:Survival Analysis
chemical_list: D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; C514871:PIP4K2A protein, human; D017853:Phosphotransferases (Alcohol Group Acceptor)