TY - JOUR
T1 - Variation at 10p12.2 and 10p14 influences risk of childhood B-cell acute lymphoblastic leukemia and phenotype
AU - Migliorini, Gabriele
AU - Fiege, Bettina
AU - Hosking, Fay J.
AU - Ma, Yussanne
AU - Kumar, Rajiv
AU - Sherborne, Amy L.
AU - da Silva Filho, Miguel Inacio
AU - Vijayakrishnan, Jayaram
AU - Koehler, Rolf
AU - Thomsen, Hauke
AU - Irving, Julie A.
AU - Allan, James M.
AU - Lightfoot, Tracy
AU - Roman, Eve
AU - Kinsey, Sally E.
AU - Sheridan, Eamonn
AU - Thompson, Pamela
AU - Hoffmann, Per
AU - Noethen, Markus M.
AU - Muehleisen, Thomas W.
AU - Eisele, Lewin
AU - Zimmermann, Martin
AU - Bartram, Claus R.
AU - Schrappe, Martin
AU - Greaves, Mel
AU - Stanulla, Martin
AU - Hemminki, Kari
AU - Houlston, Richard S.
PY - 2013
Y1 - 2013
N2 - 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.
AB - 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.
U2 - 10.1182/blood-2013-03-491316
DO - 10.1182/blood-2013-03-491316
M3 - Article
C2 - 23996088
SN - 1528-0020
VL - 122
SP - 3298
EP - 3307
JO - Blood
JF - Blood
IS - 19
ER -
