CD38 genotype-dependent regulation of CD44 and TP53 links genetic variation to aggressive phenotype in chronic...

Aim: To estimate role of CD38 rs6449182 polymorphism in CLL risk and its effect on the expression of critical tumor suppressor TP53, the promoter of cell adhesion and migration, CD44, and the immune checkpoint molecule PD-L1.

Materials and Methods: This case-control study included 50 CLL patients and 50 healthy individuals, age- and sex-matched. CLL diagnosed by flow cytometry (CD5+/CD19+/CD23+) based on WHO criteria. Genotyping of the CD38 rs6449182 polymorphism was detected through TaqMan SNP Assay. mRNA expression levels of TP53, CD44, and PD-L1 were quantified using real-time RT-PCR .

Results: Mutant G-allele was more frequent in CLL patients than in controls (19.0% vs. 10.0%), although this difference was only marginally significant P=0.075. No statistically significant association was observed between specific CD38 genotypes and the regulatory status (upregulation/downregulation) of the target genes P>0.05, while individuals with GG genotype exhibited higher median fold changes for TP53 (FC=2.97) and CD44 (FC=2.00) than the wild-type, the presence of significant inter-individual variance and broad confidence intervals indicates that these genetic variants do not serve as definitive independent predictors of gene expression in this cohort.

Conclusions: results suggest that the CD38 rs6449182 polymorphism may, at least in part, be involved in CLL risk but that it does not lead to a significant genotype-specific regulatory effect on the fold change of CD44, TP53, or PD-L1 expression. Although CD38 remains an important prognostic biomarker, the absence of a genetic-phenotypic relationship found in this study illustrates the complexity of molecular regulation by CLL. Larger studies are needed to confirm these findings.