Genome-wide association study identifies germline polymorphisms associated with relapse of childhood acute lymphoblastic leukemia

many of whom have no known risk factors, experi-ence relapse. Taking a genome-wide approach, in the present study, we evaluated the relationships between genotypes at 444 044 single nucleotide polymorphisms (SNPs) with the risk of relapse in 2535 children with newly diagnosed ALL after adjusting for genetic ancestry and treatment regimen. We identified 134 SNPs that were reproducibly associated with ALL relapse. Of 134 relapse SNPs, remained prognostic after adjusting all known relapse factors, minimal disease, patients were negative for minimal residual disease remission induction therapy. C allele at in the PYGL gene with 3.6-fold higher risk Fourteen of the antileukemic drug pharmacokinetics and/or pharmacodynamics. In the present study, we systematically identified host genetic variations related to treatment outcome of childhoodALL, most of which were prognostic independent of known risk factors for relapse, and some of which also influ-enced outcome by affecting host disposition of antileukemic drugs. All trials are registered

[1]  M. Relling,et al.  Dexamethasone exposure and asparaginase antibodies affect relapse risk in acute lymphoblastic leukemia. , 2012, Blood.

[2]  G. Rosner,et al.  Rare versus common variants in pharmacogenetics: SLCO1B1 variation and methotrexate disposition. , 2012, Genome research.

[3]  R. Aguiar,et al.  Gene Set Enrichment Analysis Unveils the Mechanism for the Phosphodiesterase 4B Control of Glucocorticoid Response in B-cell Lymphoma , 2011, Clinical Cancer Research.

[4]  Dario Campana,et al.  Minimal residual disease in acute lymphoblastic leukemia. , 2010, Hematology. American Society of Hematology. Education Program.

[5]  R. Simon,et al.  The Cross-Validated Adaptive Signature Design , 2010, Clinical Cancer Research.

[6]  M. Krajinovic,et al.  Polymorphisms in multidrug resistance-associated protein gene 4 is associated with outcome in childhood acute lymphoblastic leukemia. , 2009, Blood.

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

[8]  Cheng Cheng,et al.  Acquired variation outweighs inherited variation in whole genome analysis of methotrexate polyglutamate accumulation in leukemia. , 2009, Blood.

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

[10]  Cheng Cheng,et al.  Genome-wide interrogation of germline genetic variation associated with treatment response in childhood acute lymphoblastic leukemia. , 2009, JAMA.

[11]  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 .

[12]  Martin Stanulla,et al.  Treatment of childhood acute lymphoblastic leukemia. , 2009, Seminars in hematology.

[13]  Joshua M. Korn,et al.  Integrated genotype calling and association analysis of SNPs, common copy number polymorphisms and rare CNVs , 2008, Nature Genetics.

[14]  E. Cook,et al.  Pharmacogenetics of minimal residual disease response in children with B-precursor acute lymphoblastic leukemia: a report from the Children's Oncology Group. , 2008, Blood.

[15]  J. Taverna,et al.  Phosphodiesterase 4 Inhibitors Augment Levels of Glucocorticoid Receptor in B Cell Chronic Lymphocytic Leukemia but Not in Normal Circulating Hematopoietic Cells , 2007, Clinical Cancer Research.

[16]  R. Mei,et al.  A genomewide admixture mapping panel for Hispanic/Latino populations. , 2007, American journal of human genetics.

[17]  J. Downing,et al.  Mesenchymal cells regulate the response of acute lymphoblastic leukemia cells to asparaginase. , 2007, The Journal of clinical investigation.

[18]  C. Pui,et al.  New therapeutic strategies for the treatment of acute lymphoblastic leukaemia , 2007, Nature Reviews Drug Discovery.

[19]  Terence P. Speed,et al.  Genome analysis A genotype calling algorithm for affymetrix SNP arrays , 2005 .

[20]  Ching-Hon Pui,et al.  Gene expression and thioguanine nucleotide disposition in acute lymphoblastic leukemia after in vivo mercaptopurine treatment. , 2005, Blood.

[21]  H. Lage,et al.  Transcriptome analysis of different multidrug-resistant gastric carcinoma cells. , 2005, In vivo.

[22]  E. Cook,et al.  Pharmacogenetics of outcome in children with acute lymphoblastic leukemia. , 2004, Blood.

[23]  M. Schrappe,et al.  GSTP1 and MDR1 Genotypes and Central Nervous System Relapse in Childhood Acute Lymphoblastic Leukemia , 2005, International journal of hematology.

[24]  K. Savage,et al.  The phosphodiesterase PDE4B limits cAMP-associated PI3K/AKT-dependent apoptosis in diffuse large B-cell lymphoma. , 2005, Blood.

[25]  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.

[26]  Cheng Cheng,et al.  Gene-expression patterns in drug-resistant acute lymphoblastic leukemia cells and response to treatment. , 2004, The New England journal of medicine.

[27]  W. Młynarski,et al.  Functional C3435T polymorphism of MDR1 gene: an impact on genetic susceptibility and clinical outcome of childhood acute lymphoblastic leukemia , 2004, European journal of haematology.

[28]  Peter W. Swaan,et al.  Structural Determinants of P-Glycoprotein-Mediated Transport of Glucocorticoids , 2003, Pharmaceutical Research.

[29]  Cheng Cheng,et al.  Statistical Significance Threshold Criteria For Analysis of Microarray Gene Expression Data , 2004, Statistical applications in genetics and molecular biology.

[30]  G. Livera,et al.  Cyclic AMP-specific PDE4 Phosphodiesterases as Critical Components of Cyclic AMP Signaling* , 2003, The Journal of Biological Chemistry.

[31]  M. Houslay,et al.  PDE4 cAMP phosphodiesterases: modular enzymes that orchestrate signalling cross-talk, desensitization and compartmentalization. , 2003, The Biochemical journal.

[32]  M. Streiff,et al.  Inhibition of PDE4 phosphodiesterase activity induces growth suppression, apoptosis, glucocorticoid sensitivity, p53, and p21(WAF1/CIP1) proteins in human acute lymphoblastic leukemia cells. , 2002, Blood.

[33]  J. Harbott,et al.  Long-term results of four consecutive trials in childhood ALL performed by the ALL-BFM study group from 1981 to 1995 , 2000, Leukemia.

[34]  W. Hiddemann,et al.  Improved outcome in childhood acute lymphoblastic leukemia despite reduced use of anthracyclines and cranial radiotherapy: results of trial ALL-BFM 90. German-Austrian-Swiss ALL-BFM Study Group. , 2000, Blood.

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

[36]  J. Beijnen,et al.  The role of mdr1a P-glycoprotein in the biliary and intestinal secretion of doxorubicin and vinblastine in mice. , 2000, Drug metabolism and disposition: the biological fate of chemicals.

[37]  J. Harbott,et al.  Long-term results of four consecutive trials in childhood ALL performed by the ALL-BFM study group from 1981 to 1995. Berlin-Frankfurt-Münster. , 2000, Leukemia.

[38]  A. Borkhardt,et al.  Prednisone response is the strongest predictor of treatment outcome in infant acute lymphoblastic leukemia. , 1999, Blood.

[39]  Robert Gray,et al.  A Proportional Hazards Model for the Subdistribution of a Competing Risk , 1999 .

[40]  J. Burchenal,et al.  Treatment of acute lymphoblastic leukemia. , 1972, Annual review of medicine.