Prognostic Assessment of Three Single Nucleotide Polymorphisms (BCL2–938C>A, MTHFR 677C>T, GNAS1 T393C) in Chronic Lymphocytic Leukemia.

A number of single nucleotide polymorphisms (SNP) have been implicated to impact on the disease course in chronic lymphocytic leukemia (CLL). Nonetheless, there have been few polymorphisms for which replications of association were done in different studies. We genotyped three recently described SNPs (BCL2 –938C>A, MTHFR 677C>T, GNAS1 T393C) in a large group of CLL patients (n=273) with mature follow up and detailed analysis of molecular genetics. The cohort had a median follow-up of over 150 months and the known poor risk molecular genetics (17p–, 11q– and unmutated VH-status) were associated with poor prognosis. The allele frequencies for all three SNPs were in Hardy Weinberg equilibrium and we could not identify imbalances when we stratified for subgroups (genomic aberrations, VH status, stage according to Binet). Moreover, the polymorphisms did not affect clinical outcome (time to first treatment and overall survival) in univariate or multivariate analysis in the current cohort. Comparing CLL patients with over 100 healthy controls we found no significant differences in allele frequencies or genotype distributions for all three polymorphisms. While there have been reports showing the molecular effects and clinical consequences of the polymorphisms we studied, we did not find SNP genotype-dependent effects in a large cohort of CLL patients. Potential reasons for the discrepancy of the results are numerous. Because of the advancement of genotyping technologies, a large number of SNPs can be evaluated (multiple testing). The sample sizes of the reported association studies are often too small and frequently only one patient cohort is investigated. Moreover, negative results are often not published (publication bias). One major reason for the different results is the different genetic background of the populations due to ethnicity (selection bias). Summarized, this study supports the importance of confirmation of initial findings in an independent data set. However, results of genome-wide association studies will soon be reported with additional novel genes identified and will help making great strides in identifying the genetic determinants of CLL risk.