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

Abstract

Background: 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.

Design and methods: 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.

Results: 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.

Conclusions: 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.

Trial registration: ClinicalTrials.gov NCT00004218.

Figure 1.

Quantile-quantile plot for progression-free survival from the genome-wide association study. The dotted line represents the observed P values. The solid line represents the expected line under the null distribution.

Figure 2.

Kaplan-Meier curves. Progression-free survival (PFS) curves for (A) rs438034 (CENPF R2943G), (B) rs2064501 (IL22RA2), (C) rs2255235, (D) rs11158493 (PPP2R5E), (E) rs1949733, (F) rs10903420 (ADARB2), (G) rs1342899 and (H) rs6457160. (A) Progression-free survival curves associated with carriers of the C allele are shown as a solid line. The dashed line depicts the survival curve for those with the at risk variant genotype. (B) Progression-free survival curves associated with carriers of the T allele are shown as a solid line. The dashed line depicts the survival curve for those with the at risk variant genotype. (C) Progression-free survival curves associated with G homozygosity are shown as a solid line. The dashed and broken lines depict the survival curves for heterozygosity and A homozygosity respectively. (D) Lines are as defined in (B). (E) Progression-free survival curves associated with G homozygosity are shown as a solid line. The dashed and broken lines depict the survival curves for heterozygosity and A homozygosity, respectively. (F) Progression-free survival curves associated with carriers of the A allele are shown as a solid line. The dashed line depicts the survival curve for those with the at risk variant genotype. (G) Lines are as defined in (E). (H) Progression-free survival curves associated with carriers of the G allele are shown as a solid line. The dashed line depicts the survival curve for those with at risk variant genotype.

Figure 3.

Relationship between lymphocyte mRNA expression levels of PPP2R5E and rs1012145 genotype.