Article

Identification of germline susceptibility loci in ETV6-RUNX1-rearranged childhood acute lymphoblastic leukemia.

Institute of Clinical Molecular Biology, Christian-Albrechts-University Kiel, Kiel, Germany.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K (Impact Factor: 10.16). 11/2011; 26(5):902-9. DOI: 10.1038/leu.2011.302
Source: PubMed

ABSTRACT Acute lymphoblastic leukemia (ALL) is a malignant disease of the white blood cells. The etiology of ALL is believed to be multifactorial and likely to involve an interplay of environmental and genetic variables. We performed a genome-wide association study of 355 750 single-nucleotide polymorphisms (SNPs) in 474 controls and 419 childhood ALL cases characterized by a t(12;21)(p13;q22) - the most common chromosomal translocation observed in childhood ALL - which leads to an ETV6-RUNX1 gene fusion. The eight most strongly associated SNPs were followed-up in 951 ETV6-RUNX1-positive cases and 3061 controls from Germany/Austria and Italy, respectively. We identified a novel, genome-wide significant risk locus at 3q28 (TP63, rs17505102, P(CMH)=8.94 × 10(-9), OR=0.65). The separate analysis of the combined German/Austrian sample only, revealed additional genome-wide significant associations at 11q11 (OR8U8, rs1945213, P=9.14 × 10(-11), OR=0.69) and 8p21.3 (near INTS10, rs920590, P=6.12 × 10(-9), OR=1.36). These associations and another association at 11p11.2 (PTPRJ, rs3942852, P=4.95 × 10(-7), OR=0.72) remained significant in the German/Austrian replication panel after correction for multiple testing. Our findings demonstrate that germline genetic variation can specifically contribute to the risk of ETV6-RUNX1-positive childhood ALL. The identification of TP63 and PTPRJ as susceptibility genes emphasize the role of the TP53 gene family and the importance of proteins regulating cellular processes in connection with tumorigenesis.

2 Bookmarks
 · 
361 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background:Evidence for an inherited genetic risk for pediatric acute lymphoblastic leukemia has been provided in several studies. Most of them focused on coding regions. However, those regions represent only 1.5% of the entire genome. In ALL, it has been suggested that the expression of microRNAs is dysregulated, which suggests that they may have a role in ALL risk. Changes in miRNA function may occur through SNPs. Therefore, the aim of this study was to evaluate whether polymorphisms in pre-miRNAs, and/or miRNA processing genes, contribute to a predisposition for childhood ALL.Methods:In this study, we analyzed 118 SNPs in pre-miRNAs and miRNA processing genes in 213 B-ALL patients and 387 controls.Results:We found 11 SNPs significantly associated with ALL susceptibility. These included three SNPs present in miRNA genes (miR-612, miR-499, and miR-449b) and eight SNPs present in six miRNA biogenesis pathway genes (TNRC6B, DROSHA, DGCR8, EIF2C1, CNOT1, and CNOT6). Among the 118 SNPs analyzed, rs12803915 in mir-612 and rs3746444 in mir-499 exhibited a more significant association, with a p value <0.01.Conclusion:The results of this study indicate that SNP rs12803915 located in pre-mir-612, and SNP rs3746444 located in pre-mir-499, may represent novel markers of B-ALL susceptibility.Pediatric Research (2014); doi:10.1038/pr.2014.43.
    Pediatric Research 03/2014; · 2.67 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Interactions between common germline variants in ARID5B and IKZF1 and other known childhood acute lymphoblastic leukemia (ALL) risk factors were queried using biospecimens and data from 770 ALL cases and 384 controls. Case-control comparisons revealed dose-dependent associations between ARID5B rs10821936, ARID5B rs10994982, and IKZF1 rs11978267 and childhood ALL overall, and B lineage and B lineage hyperdiploid ALL examined separately (all allelic odds ratios ≥1.33, Ptrend≤0.001). No heterogeneity was observed between ORs for males and females (all Pinteraction≥0.48). Likewise, no significant genotype-birth weight interactions were detected (all Pinteraction≥0.12) among cases. These results indicate similar ALL risk across strata of known risk factors.
    Leukemia research 05/2013; · 2.36 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Acute lymphoblastic leukemia (ALL) is a major cause of mortality and morbidity in childhood, and the causes of ALL are not completely understood. microRNAs (miRNAs) regulate various biological processes including organ development, cell growth regulation, cell differentiation, apoptosis, and tumorigenesis. We performed a case-control study with 570 childhood ALL cases and 673 cancer-free controls to investigate the association between hsa-miR-196a2 rs11614913 T>C polymorphism and ALL risk. The bioinformatics was used to estimate the potential target of hsa-miR-196a2. In the present study, the hsa-miR-196a2 variant TC heterozygote, and CC/TC genotypes were found to be associated with a significantly increased childhood ALL risk, compared with the TT wild-type homozygote (adjusted OR=1.50, 95% CI=1.15-1.95 for TC and OR=1.40, 95%CI=1.09-1.79 for CC/TC). Further, the difference was pronounced in younger (≤ 6) subjects or parental non-drinker. The significance of the increased risk is more obvious than the higher treatment branch. Additionally, we found that the rs11614913 TC genotype can increase B-phenotype ALL risk (OR=1.37, 95% CI=1.07-1.76). Finally, combination of three bioinformatics approaches revealed that HOXC8 may be the target gene of hsa-miR-196a2. Taken together, our finding suggested that hsa-miR-196a2 rs11614913 T>C may increase the risk of childhood ALL. Large studies with the function of hsa-miR-196a2 are needed in the further study.
    Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 11/2013; · 3.90 Impact Factor

Full-text (2 Sources)

View
76 Downloads
Available from
May 30, 2014