Title |
Variation at 10p12.2 and 10p14 influences risk of childhood B-cell acute lymphoblastic leukemia and phenotype
|
---|---|
Published in |
Blood, August 2013
|
DOI | 10.1182/blood-2013-03-491316 |
Pubmed ID | |
Authors |
Gabriele Migliorini, Bettina Fiege, Fay J. Hosking, Yussanne Ma, Rajiv Kumar, Amy L. Sherborne, Miguel Inacio da Silva Filho, Jayaram Vijayakrishnan, Rolf Koehler, Hauke Thomsen, Julie A. Irving, James M. Allan, Tracy Lightfoot, Eve Roman, Sally E. Kinsey, Eamonn Sheridan, Pamela Thompson, Per Hoffmann, Markus M. Nöthen, Thomas W. Mühleisen, Lewin Eisele, Martin Zimmermann, Claus R. Bartram, Martin Schrappe, Mel Greaves, Martin Stanulla, Kari Hemminki, Richard S. Houlston |
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. |
X Demographics
Geographical breakdown
Country | Count | As % |
---|---|---|
United States | 2 | 100% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Members of the public | 1 | 50% |
Scientists | 1 | 50% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
United States | 2 | 2% |
Germany | 1 | <1% |
United Kingdom | 1 | <1% |
Sweden | 1 | <1% |
Japan | 1 | <1% |
Belgium | 1 | <1% |
Unknown | 102 | 94% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Researcher | 25 | 23% |
Student > Ph. D. Student | 21 | 19% |
Student > Master | 12 | 11% |
Student > Doctoral Student | 10 | 9% |
Student > Bachelor | 8 | 7% |
Other | 15 | 14% |
Unknown | 18 | 17% |
Readers by discipline | Count | As % |
---|---|---|
Biochemistry, Genetics and Molecular Biology | 34 | 31% |
Medicine and Dentistry | 27 | 25% |
Agricultural and Biological Sciences | 17 | 16% |
Immunology and Microbiology | 2 | 2% |
Pharmacology, Toxicology and Pharmaceutical Science | 2 | 2% |
Other | 5 | 5% |
Unknown | 22 | 20% |