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Association between single nucleotide polymorphism-genotype and outcome of patients with chronic lymphocytic leukemia in a randomized chemotherapy trial.

ABSTRACT: There is variability in the outcome of patients with chronic lymphocytic leukemia with apparently the same stage of disease. Identifying genetic variants that influence patients' outcome and response to treatment may provide important insights into the biology of the disease.We investigated the possibility that genetic variation influences outcome by conducting a genome-wide analysis of 346,831 single nucleotide polymorphisms in 356 patients entered into a phase III trial comparing the efficacy of fludarabine, chlorambucil, and fludarabine with cyclophosphamide as first-line treatment. Genotypes were linked to individual patients' outcome data and response to chemotherapy. The association between genotype and progression-free survival was assessed by Cox regression analysis adjusting for treatment and clinicopathology.The strongest associations were shown for rs1949733 (ACOX3; P=8.22x10-7), rs1342899 (P=7.72×10(-7)) and rs11158493 (PPP2R5E; P=8.50×10(-7)). In addition, the 52 single nucleotide polymorphisms associated at P<10(-4) included rs438034 (CENPF; P=4.86×10(-6)), previously correlated with cancer progression, and rs2255235 (B2M; P=3.10×10(-5)) and rs2064501 (IL22RA2; P=4.81×10(-5)) which map to B-cell genes.Our findings provide evidence that genetic variation is a determinant of progression-free survival of patients with chronic lymphocytic leukemia. Specific associations warrant further analyses.

SUBMITTER: Wade R

PROVIDER: S-EPMC3186311 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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Association between single nucleotide polymorphism-genotype and outcome of patients with chronic lymphocytic leukemia in a randomized chemotherapy trial.

Wade Rachel R Di Bernardo Maria Chiara MC Richards Sue S Rossi Davide D Crowther-Swanepoel Dalemari D Gaidano Gianluca G Oscier David G DG Catovsky Daniel D Houlston Richard S RS

Haematologica 20110609 10

<h4>Background</h4>There is variability in the outcome of patients with chronic lymphocytic leukemia with apparently the same stage of disease. Identifying genetic variants that influence patients' outcome and response to treatment may provide important insights into the biology of the disease.<h4>Design and methods</h4>We investigated the possibility that genetic variation influences outcome by conducting a genome-wide analysis of 346,831 single nucleotide polymorphisms in 356 patients entered ...[more]

PMID: 21659360

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Project description:BackgroundChronic myeloid leukemia (CML) is a myeloproliferative neoplasm where pathogenesis is based on the oncoprotein termed BCR-ABL1.1 TET2 initiates DNA demethylation and is frequently mutated in hematological malignancies, including CML. The relation between TET2 acquisition and CML transformation and/or imatinib resistance is needed to be investigated.2.AimTo evaluate Ten Eleven Translocation 2 gene (TET2) single nucleotide polymorphism (SNP) (rs2454206, rs34402524, rs61744960) in chronic myeloid leukemia (CML) in relation to the disease prognostic criteria.Materials & methodThe study included 84 subjects; 54 CML in chronic phase and 30 healthy subjects as control group matched for age and sex. Routine investigations, including CBC, bone marrow aspiration, biochemical investigations, and molecular study, were performed in CML patients to identify the disease stage. DNA extraction and SNP assay for TET2 gene polymorphism were done using (Thermo-Fisher predesigned SNP, USA) PCR prism 7500.ResultsThe mean age was 45.98±15.7 yrs in CML patients and 39.3±6.587 yrs in the control group (p>0.05). TET2 SNP rs 34402524 was either heterozygous or homozygous in CML (48%, 46.2% respectively) but was mainly homozygous among control (80%) group (p=0.012). TET2 SNP rs 2454206 wild type within CML was detected in 65.4% of patients and in controls was 63.3% (p=0.046). TET2 SNP rs 61744960 showed a homozygous pattern among all groups (CML and control) (p=0.528). TET2 SNP in CML cases did not alter the prognostic criteria as no statistical significance was noted (p>0.05) yet, it was significantly related to spleen size in rs 34402524 where the homozygous group had larger spleen size and higher BCR-ABL1 levels six months after starting TKIs (p<0.05).Conclusions/recommendationTET2 SNP is common among Egyptian chronic myeloid leukemia. TET2 SNP rs 3442524 was associated with larger spleen size and higher BCR-ABL1 levels after six months of starting TKIs suggesting disease progression.

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Association between single nucleotide polymorphism-genotype and outcome of patients with chronic lymphocytic leukemia in a randomized chemotherapy trial.

Publications

Association between single nucleotide polymorphism-genotype and outcome of patients with chronic lymphocytic leukemia in a randomized chemotherapy trial.

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