Browsing by Author "Gail E. Tomlinson"

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    Candidate gene association analysis of acute lymphoblastic leukemia identifies new susceptibility locus at 11p15 (LMO1)
    (2011-09-09) Joke Beuten; Jonathan A L Gelfond; Duangjai Piwkham; Brad H. Pollock; Naomi J. Winick; Anderson B. Collier; Gail E. Tomlinson; University of Texas Health Science Center at San Antonio; Mahidol University; UT Southwestern Medical School; Lehigh Valley Hospital and Health Network
    To determine the contribution of susceptibility loci in explaining the genetic basis of acute lymphoblastic leukemia (ALL), we genotyped 29 high-potential candidate genes with 672 tagged single-nucleotide polymorphisms (SNPs) in a sample (163 cases and 251 healthy controls) of Caucasian children. Fifty SNPs in 15 genes were significantly associated with ALL risk at the P < 0.05 level. After correction for multiple testing, rs442264 within the LIM domain only 1 (LMO1) gene at 11p15 remained significant [odds ratio (OR) = 1.90, P= 3× 10 -5 ]. In addition, a major haplotype within LMO1 comprising 14 SNPs with individual risk associations was found to significantly increase ALL risk (OR 5 1.79, P 5 0.0006). A stratified analysis on subtype indicated that risk associations of LMO1 variants are significant in children with precursor B-cell leukemia. These data show that genetic variants within LMO1 are associated with ALL and identify this gene as a strong candidate for precursor B-cell leukemogenesis. © The Author 2011. Published by Oxford University Press. All rights reserved.
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    Multilocus association of genetic variants in MLL, CREBBP, EP300, and TOP2A with childhood acute lymphoblastic leukemia in hispanics from Texas
    (2011-06-01) Duangjai Piwkham; Jonathan A L Gelfond; Budsaba Rerkamnuaychoke; Samart Pakakasama; Vivienne I. Rebel; Brad H. Pollock; Naomi J. Winick; Anderson B. Collier; Gail E. Tomlinson; Joke Beuten; University of Texas Health Science Center at San Antonio; Mahidol University; UT Southwestern Medical Center; Lehigh Valley Hospital and Health Network
    Background: Hispanic children have both a higher incidence and a poorer outcome in acute lymphoblastic leukemia (ALL). Moreover, a higher incidence for therapy-related acute myeloid leukemia with 11q23 translocations after treatment with topoisomerase II (topo II) inhibitors has been observed in Hispanic children with ALL. We sought to determine the potential role of genetic variants within the topoisomerase IIa gene (TOP2A), within the mixed lineage leukemia gene (MLL) and two of its translocation partners, cyclin AMP response element-binding protein gene (CREBBP) and E1A binding protein gene (EP300) in the increased sensitivity of Hispanic children with ALL to topo II inhibitors. Methods: Fifty-two tagged single nucleotide polymorphisms (SNP) covering the four genes were genotyped in 241 samples (66 children with ALL and 175 age matched controls) of self-identified Hispanic origin. Results: Two SNPs within MLL (rs525549 and rs6589664) and three SNPs within EP300 (rs5758222, rs7286979, and rs20551) were significantly associated with ALL (P = 0.001-0.04). A significant gene-dosage effect for increasing numbers of potential high-risk genotypes (OR = 16.66; P = 2 × 10 -5 ) and a major haplotype significantly associated with ALL (OR = 5.68; P = 2 × 10 -6 ) were found. Replication in a sample of 137 affected White children and 239 controls showed that only rs6589664 (MLL) was significantly associated in this ethnic group. Conclusions: Our findings indicate that the association between ALL and common genetic variants within MLL and EP300 is population specific. Impact: Replication of our findings in independent Hispanic populations is warranted to elucidate the role of these variants in ALL susceptibility and define their importance in the ethnic specific differences in ALL risk. ©2011 AACR.
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    Mutation screening and association study of the folylpolyglutamate synthetase (FPGS) gene with susceptibility to childhood acute lymphoblastic leukemia
    (2015-01-01) Duangjai Piwkham; Teerapong Siriboonpiputtana; Joke Beuten; Samart Pakakasama; Jonathan A.L. Gelfond; Karan Paisooksantivatana; Gail E. Tomlinson; Budsaba Rerkamnuaychoke; Mahidol University; University of Texas Health Science Center at San Antonio
    Background: Folylpolyglutamate synthetase (FPGS), an important enzyme in the folate metabolic pathway, plays a central role in intracellular accumulation of folate and antifolate in several mammalian cell types. Loss of FPGS activity results in decreased cellular levels of antifolates and consequently to polyglutamatable antifolates in acute lymphoblastic leukemia (ALL). Materials and Methods: During May 1997 and December 2003, 134 children diagnosed with ALL were recruited from one hospital in Thailand. We performed a mutation analysis in the coding regions of the FPGS gene and the association between single nucleotide polymorphisms (SNPs) within FPGS in a case-control sample of childhood ALL patients. Mutation screening was conducted by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) and subsequently with direct sequencing (n=72). Association analysis between common FPGS variants and ALL risk was done in 98 childhood ALL cases and 95 healthy volunteers recruited as controls. Results: Seven SNPs in the FPGS coding region were identified by mutation analysis, 3 of which (IVS13+55C > T, g.1297T > G, and g.1508C > T) were recognized as novel SNPs. Association analysis revealed 3 of 6 SNPs to confer significant increase in ALL risk these being rs7039798 (p= 0.014, OR=2.14), rs1544105 (p=0.010, OR= 2.24), and rs10106 (p=0.026, OR= 1.99). Conclusions: These findings suggested that common genetic polymorphisms in the FPGS coding region including rs7039789, rs1544105, and rs10106 are significantly associated with increased ALL risk in Thai children.