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: 10.43). 11/2011; 26(5):902-9. DOI: 10.1038/leu.2011.302
Source: PubMed


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.

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    • "Acute lymphoblastic leukemia is one of the most important blood cancers in human kind (6) and it is a malignant illness of white blood cells (18). This kind of leukemia includes 32 percent of cancers in children under 15 years old (19) and it includes 80 percent of cases of blood cancers in children (5, 7, 8). "
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    ABSTRACT: Acute lymphoblastic leukemia (ALL) is one of the most prevalent hematologic malignancies in children. Although the cure rate of ALL has improved over the past decades, the most important reason for ALL treatment failure is multidrug resistance (MDR) phenomenon. The current study aims to explain the mechanisms involved in multidrug resistance of childhood ALL, and introduces ATP-binding cassette transporterA2 (ABCA2) as an ABC transporter gene which may have a high impact on MDR. Benefiting from articles published inreputable journals from1994 to date and experiments newly performed by our group, a comprehensive review is written about ABCA2 and its role in MDR regarding childhood ALL. ABCA2 transports drugs from the cytoplasm into the lysosomal compartment, where they may become degraded and exported from the cell. The aforementioned mechanism may contribute to MDR. It has been reported that ABCA2 may induce resistance to mitoxantrone, estrogen derivatives and estramustine. It is resistant to the aforementioned compounds. Furthermore, the overexpression ofABCA2 in methotrexate, vinblastine and/or doxorubicin treated Jurkat cells are observed in several publications. The recent study of our group showsthatthe overexpression ofABCA2 gene in children with ALL increases the risk of MDR by 15 times. ABCA2 is the second identified member of the ABCA; ABC transporters' subfamily. ABCA2 gene expression profile is suggested to be an unfavorable prognostic factor in ALL treatment. Better understanding of the MDR mechanisms and the factors involved may improve the therapeutic outcome of ALL by modifying the treatment protocols.
    07/2014; 4(3):118-26.
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    • "Several independent genome-wide association studies (GWAS) have confirmed a number of genetic variants that affect genetic susceptibility to ALL, although they are individually modest in their effects. In the most recent GWAS on ETV6-RUNX1-positive ALL, a few (ETV6-RUNX1-specific) susceptibility loci, predominantly related to pathways controlling embryonic and B-cell development and differentiation, were identified [81]. Based on copy number alterations, cases could be categorised into four distinct subgroups revealing genetic diversity within ETV6-RUNX1-positive ALL which is of importance for improving treatment strategies [82] [83]. "
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    ABSTRACT: Recent findings related to childhood leukaemia incidence near nuclear installations have raised questions which can be answered neither by current knowledge on radiation risk nor by other established risk factors. In 2012, a workshop was organised on this topic with two objectives: (a) review of results and discussion of methodological limitations of studies near nuclear installations; (b) identification of directions for future research into the causes and pathogenesis of childhood leukaemia. The workshop gathered 42 participants from different disciplines, extending widely outside of the radiation protection field. Regarding the proximity of nuclear installations, the need for continuous surveillance of childhood leukaemia incidence was highlighted, including a better characterisation of the local population. The creation of collaborative working groups was recommended for consistency in methodologies and the possibility of combining data for future analyses. Regarding the causes of childhood leukaemia, major fields of research were discussed (environmental risk factors, genetics, infections, immunity, stem cells, experimental research). The need for multidisciplinary collaboration in developing research activities was underlined, including the prevalence of potential predisposition markers and investigating further the infectious aetiology hypothesis. Animal studies and genetic/epigenetic approaches appear of great interest. Routes for future research were pointed out.
    Journal of Radiological Protection 06/2014; 34(3):R53. DOI:10.1088/0952-4746/34/3/R53 · 1.70 Impact Factor
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    • "Recently, single-nucleotide polymorphisms (SNPs) in two genetic loci, AT-rich interactive domain 5B (ARID5B) and Ikaros family zinc finger protein 1 (IKZF1), were found to be strongly associated with ALL risk (Papaemmanuil et al. 2009; Treviño et al. 2009). The association of ARID5B with ALL risk was a novel finding and was confirmed in subsequent studies (Han et al. 2010; Healy et al. 2010; Prasad et al. 2010; Vijayakrishnan et al. 2010; Yang et al. 2010; Pastorczak et al. 2011; Ellinghaus et al. 2012; Orsi et al. 2012; Xu et al. 2012). "
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    ABSTRACT: Single-nucleotide polymorphisms (SNPs) in AT-rich interactive domain 5B (ARID5B) have been associated with risk for pediatric acute lymphoblastic leukemia (ALL). After reviewing previous studies, we realized that the most significant associations were restricted to intron 3, but the mechanism(s) by which those SNPs affect ALL risk remain to be elucidated. Therefore, the aim of this study was to analyze the association between genetic variants of the intron 3 region of ARID5B and the incidence of B-ALL in a Spanish population. We also aimed to find a functional explanation for the association, searching for copy number variations (CNVs), and changes in ARID5B expression associated with the genotypes of the SNPs. We analyzed 10 SNPs in intron 3 of ARID5B in a Spanish population of 219 B-ALL patients and 397 unrelated controls with the Taqman Open Array platform. CNVs were analyzed in 23 patients and 17 controls using the Cytogenetics Whole-genome 2.7 M platform. Expression of ARID5B transcript 1 was quantified by qPCR and related to SNPs genotype in seven ALL cell lines. Association between intron 3 and B-ALL risk was confirmed for all of the SNPs evaluated in our Spanish population. We could not explain this association by the presence of CNVs. We neither detected changes in the expression of ARID5B isoform associated with the genotype of the SNPs. The intron 3 of ARID5B gene was found to be strongly associated with B-ALL risk in the Spanish population examined. However, neither CNVs nor changes in mRNA expression were found to be responsible for this association.
    Journal of Cancer Research and Clinical Oncology 09/2013; 139(11). DOI:10.1007/s00432-013-1512-3 · 3.08 Impact Factor
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