Germline genomic variants associated with childhood acute lymphoblastic leukemia

Using the Affymetrix 500K Mapping array and publicly available genotypes, we identified 18 SNPs whose allele frequency differed significantly(P < 1 × 10−5) between pediatric acute lymphoblastic leukemia (ALL) cases (n = 317) and non-ALL controls (n = 17,958). Two SNPs in ARID5B not only differed between ALL and non-ALL groups (rs10821936, P = 1.4 × 10−15, odds ratio (OR) = 1.91; rs10994982, P = 5.7 × 10−9, OR = 1.62) but also distinguished B-hyperdiploid ALL from other subtypes (rs10821936, P = 1.62 × 10−5, OR = 2.17; rs10994982, P = 0.003, OR 1.72). These ARID5B SNPs also distinguished B-hyperdiploid ALL from other subtypes in an independent validation cohort (n = 124 children with ALL; P = 0.003 and P = 0.0008, OR 2.45 and 2.86, respectively) and were associated with methotrexate accumulation and gene expression pattern in leukemic lymphoblasts. We conclude that germline variants affect susceptibility to, and characteristics of, specific ALL subtypes.

[1]  Han-chun Chen,et al.  Genetic polymorphisms of metabolic enzymes CYP1A1, CYP2D6, GSTM1 and GSTT1 and leukemia susceptibility , 2008, European journal of cancer prevention : the official journal of the European Cancer Prevention Organisation.

[2]  K. Mossman The Wellcome Trust Case Control Consortium, U.K. , 2008 .

[3]  L. Matherly,et al.  In vitro formation of polyglutamyl derivatives of methotrexate and 7-hydroxymethotrexate in human lymphoblastic leukemia cells. , 1983, Cancer research.

[4]  J. Downing,et al.  Classification, subtype discovery, and prediction of outcome in pediatric acute lymphoblastic leukemia by gene expression profiling. , 2002, Cancer cell.

[5]  Christopher B. Miller,et al.  Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia. , 2009, The New England journal of medicine.

[6]  P. Dallas,et al.  The DNA-binding properties of the ARID-containing subunits of yeast and mammalian SWI/SNF complexes. , 2004, Nucleic acids research.

[7]  I. Kola,et al.  Gene targeting of Desrt, a novel ARID class DNA-binding protein, causes growth retardation and abnormal development of reproductive organs. , 2001, Genome research.

[8]  W. Evans,et al.  A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome: a genome-wide classification study. , 2009, The Lancet. Oncology.

[9]  John P. Rice,et al.  Genome-wide scan and conditional analysis in bipolar disorder: evidence for genomic interaction in the National Institute of Mental Health genetics initiative bipolar pedigrees , 2003, Biological Psychiatry.

[10]  K Georgopoulos,et al.  The Ikaros gene encodes a family of lymphocyte-restricted zinc finger DNA binding proteins, highly conserved in human and mouse. , 1996, Journal of immunology.

[11]  Aravind Subramanian,et al.  Identification of distinct molecular phenotypes in acute megakaryoblastic leukemia by gene expression profiling. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[12]  Simon C. Potter,et al.  Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls , 2007, Nature.

[13]  F P Perera,et al.  Environment and cancer: who are susceptible? , 1997, Science.

[14]  P. Campbell Somatic and germline genetics at the JAK2 locus , 2009, Nature Genetics.

[15]  Pablo V Gejman,et al.  Genomewide linkage scan of 409 European-ancestry and African American families with schizophrenia: suggestive evidence of linkage at 8p23.3-p21.2 and 11p13.1-q14.1 in the combined sample. , 2006, American journal of human genetics.

[16]  C. Pui,et al.  Treatment of acute lymphoblastic leukemia. , 2006, The New England journal of medicine.

[17]  M. Greaves Science, medicine, and the future: Childhood leukaemia , 2002 .

[18]  R. Gelber,et al.  Improved outcome for children with acute lymphoblastic leukemia: results of Dana-Farber Consortium Protocol 91-01. , 2001, Blood.

[19]  M. Greaves Speculations on the cause of childhood acute lymphoblastic leukemia. , 1988, Leukemia.

[20]  P. Dallas,et al.  ARID proteins: a diverse family of DNA binding proteins implicated in the control of cell growth, differentiation, and development. , 2002, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[21]  M. Relling,et al.  Blast cell methotrexate-polyglutamate accumulation in vivo differs by lineage, ploidy, and methotrexate dose in acute lymphoblastic leukemia. , 1994, The Journal of clinical investigation.

[22]  Francis J McMahon,et al.  Genomewide linkage analyses of bipolar disorder: a new sample of 250 pedigrees from the National Institute of Mental Health Genetics Initiative. , 2003, American journal of human genetics.

[23]  Cheng Cheng,et al.  Improved outcome for children with acute lymphoblastic leukemia: results of Total Therapy Study XIIIB at St Jude Children's Research Hospital. , 2004, Blood.

[24]  Rakesh Nagarajan,et al.  Computational identification of the normal and perturbed genetic networks involved in myeloid differentiation and acute promyelocytic leukemia , 2008, Genome Biology.

[25]  A. Chokkalingam,et al.  MDR1 Gene Variants, Indoor Insecticide Exposure, and the Risk of Childhood Acute Lymphoblastic Leukemia , 2007, Cancer Epidemiology Biomarkers & Prevention.

[26]  E. Moran,et al.  DNA-binding properties of ARID family proteins , 2005, Nucleic acids research.

[27]  K. Georgopoulos,et al.  The Ikaros gene encodes a family of functionally diverse zinc finger DNA-binding proteins , 1994, Molecular and cellular biology.

[28]  M. Schrappe,et al.  Polymorphisms within glutathione S-transferase genes (GSTM1, GSTT1, GSTP1) and risk of relapse in childhood B-cell precursor acute lymphoblastic leukemia: a case-control study. , 2000, Blood.

[29]  Elmar Bucher,et al.  Genome‐wide analysis identifies 16q deletion associated with survival, molecular subtypes, mRNA expression, and germline haplotypes in breast cancer patients , 2008, Genes, chromosomes & cancer.

[30]  R. Sobti,et al.  Combined effect of GSTM1, GSTT1 and GSTP1 polymorphisms on histological subtypes of lung cancer. , 2008, Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals.

[31]  M. Schrappe,et al.  Polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and susceptibility to pediatric acute lymphoblastic leukemia in a German study population , 2005, BMC Medical Genetics.

[32]  G. M. Taylor,et al.  Methylenetetrahydrofolate reductase (MTHFR) polymorphisms and risk of molecularly defined subtypes of childhood acute leukemia , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[33]  B. Johansson,et al.  Evidence for a single‐step mechanism in the origin of hyperdiploid childhood acute lymphoblastic leukemia , 2005, Genes, chromosomes & cancer.

[34]  D. Labuda,et al.  Role of DNA mismatch repair genetic polymorphisms in the risk of childhood acute lymphoblastic leukaemia , 2003, British journal of haematology.

[35]  Min Sung Kim,et al.  Frameshift mutation of UVRAG, an autophagy-related gene, in gastric carcinomas with microsatellite instability. , 2008, Human pathology.

[36]  M. Burns,et al.  Case-Control Study , 2020, Definitions.

[37]  J J Shuster,et al.  Minimal residual disease detection in childhood precursor–B-cell acute lymphoblastic leukemia: relation to other risk factors. A Children's Oncology Group study , 2003, Leukemia.

[38]  J. Downing,et al.  Classification of pediatric acute lymphoblastic leukemia by gene expression profiling. , 2003, Blood.

[39]  R. Arceci Deletion of IKZF1 and Prognosis in Acute Lymphoblastic Leukemia , 2010 .

[40]  P. Donnelly,et al.  Inference of population structure using multilocus genotype data. , 2000, Genetics.

[41]  Cheng Cheng,et al.  Treating childhood acute lymphoblastic leukemia without cranial irradiation. , 2009, The New England journal of medicine.

[42]  Christopher B. Miller,et al.  BCR–ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros , 2008, Nature.

[43]  Greaves Mf Speculations on the cause of childhood acute lymphoblastic leukemia. , 1988 .

[44]  A. Fleming,et al.  Childhood leukaemia , 1991, The Lancet.

[45]  M. Relling,et al.  Accumulation of methotrexate polyglutamates in lymphoblasts is a determinant of antileukemic effects in vivo. A rationale for high-dose methotrexate. , 1996, The Journal of clinical investigation.

[46]  R. Arceci,et al.  Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children's Oncology Group study , 2009 .

[47]  Christopher B. Miller,et al.  Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia , 2007, Nature.

[48]  Daniel Sinnett,et al.  Promoter SNPs in G1/S checkpoint regulators and their impact on the susceptibility to childhood leukemia. , 2007, Blood.

[49]  John D Potter,et al.  Genetic susceptibility to cancer: the role of polymorphisms in candidate genes. , 2008, JAMA.

[50]  J. Downing,et al.  Folate pathway gene expression differs in subtypes of acute lymphoblastic leukemia and influences methotrexate pharmacodynamics. , 2005, The Journal of clinical investigation.