4.23 MDM2 Promotor Polymorphism and Disease Characteristics in CLL: Individual Patient Data Meta-Analysis of 2598 CLL Patients

Abstract

Similar to other cancers, a number of single nucleotide polymorphisms (SNP) of different genes have been associated with disease predisposition as well as disease characteristics in chronic lymphocytic leukemia (CLL). While the potential effects of gene polymorphisms is widely acknowledged, most studies investigating the impact of single SNPs in CLL have been controversial1,2. In the current study we intend to settle the dispute on the effect of the MDM2 SNP309 on disease characteristics by using individual patient data (IPD) meta-analysis. To this end we have collected data from 10 European centers, which contributed predetermined clinical and genetic information on their patient cohorts. We have compiled patient data sets from 10 single-center cohorts (n = 140-418) adding up to 2598 patients with CLL. Median follow up was 98 months in the whole set, ranging from 57 months to 145 months. Patient sex, age, date of diagnosis, date of first treatment and last follow-up as well as status were collected according to our meta-analysis study protocol. Genetic data for MDM2 SNP genotype, immunoglobulin heavy chain variable region (IGVH) gene status and fluorescence in situ hybridization (FISH) results (11q22.q23; 17p13) were also added. The genotype distribution of the MDM2 SNP309 was comparable between the 10 cohorts (P = 0.11). There were no differences in risk of death based on the polymorphism (overall survival: stratified log-rank test; P = 0.39). Specifically, the GG genotype group had a median overall survival time of 123 months compared with 150 months for the TG group and 135 months for the TT genotype. Because of the known interaction of MDM2 with the p53 pathway we also assessed the impact of the SNP in the group with and without 17p deletion. Again no impact of the genotype could be demonstrated (data not shown). We performed cohort-stratified Cox proportional hazards regression analysis to assess the potential impact of the MDM2 genotype considering known prognostic factors. The first model included MDM2 genotype, sex, age and IGHV status as well as the stratification according to centers (Table 1A). Advanced age, male sex and unmutated IGHV status were associated with inferior survival but not the MDM2 genotype. In a separate model, we included FISH aberrations (17p-, 11q-). In this model, sex, age, IGHV status, and 17p- were associated with increased risk of death but the MDM2 SNP309 genotype was not associated with outcome (Table 1B). Conclusion: In contrast to some single center cohorts, we did not find an impact of the polymorphism on disease characteristics in CLL by IPD meta-analysis. More specifically there was no influence of the SNP on age of onset, time to first treatment, or overall survival. Our findings suggest that the MDM2 SNP309 is unlikely to influence disease characteristics in CLL. Abstract 4.23Cox Regression Models for Overall Survival, Stratified by Center A) Model fit based on data from all 10 cohort centers Effect HR ⁎ HR = hazard ratio; CI = confidence interval. 95% CI ⁎ HR = hazard ratio; CI = confidence interval. P Age 10 yrs 1.85 1.72 - 1.99 < 0.00 Sex M:F 1.45 1.25 - 1.67 < 0.00 IGHV Mutation Status UM:M 2.83 2.44 - 3.28 < 0.00 MDM2 SNP309 0.5 TG:GG 0.88 0.71 - 1.10 TT:GG 0.89 0.72 - 1.11 B) Model fit including FISH data (available for 9 centers) Effect HR⁎ HR = hazard ratio; CI = confidence interval. 95% CI⁎ HR = hazard ratio; CI = confidence interval. P Age 10 yrs 1.94 1.78 - 2.12 < 0.00 Sex M:F 1.52 1.28 - 1.81 < 0.00 IGHV Mutation Status UM:M 3.19 2.66 - 3.82 < 0.00 17p13- yes:no 3.15 2.46 - 4.05 < 0.00 11q22.q23- yes:no 1.43 1.15 - 1.77 0.00 MDM2 SNP309 0.5 TG:GG 0.89 0.69 - 1.14 TT:GG 0.86 0.67 - 1.11 HR = hazard ratio; CI = confidence interval. Open table in a new tab