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Variation at 10p12.2 and 10p14 influences risk of childhood B-cell acute lymphoblastic leukemia and phenotype

Lookup NU author(s): Professor Julie Irving, Professor James Allan

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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 x 10(-9)) and 10p14marked by rs3824662(OR = 1.31; P = 8.62 x 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.


Publication metadata

Author(s): Migliorini G, Fiege B, Hosking FJ, Ma Y, Kumar R, Sherborne AL, da Silva MI, Vijayakrishnan J, Koehler R, Thomsen H, Irving JA, Allan JM, Lightfoot T, Roman E, Kinsey SE, Sheridan E, Thompson P, Hoffmann P, Nothen MM, Muhleisen TW, Eisele L, Zimmermann M, Bartram CR, Schrappe M, Greaves M, Stanulla M, Hemminki K, Houlston RS

Publication type: Article

Publication status: Published

Journal: Blood

Year: 2013

Volume: 122

Issue: 19

Pages: 3298-3307

Print publication date: 07/11/2013

Acceptance date: 12/08/2013

ISSN (print): 0006-4971

ISSN (electronic): 1528-0020

Publisher: American Society of Hematology

URL: http://dx.doi.org/10.1182/blood-2013-03-491316

DOI: 10.1182/blood-2013-03-491316


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