Analysis of TP53 Codon72, and p21 Codon31 Polymorphisms in CLL Patients Exposed to Ionizing Radiation Due to the Chernobyl NPP Accident

Abstract 4580

Chronic lymphocytic leukemia (CLL) was shown to be the most common leukemia among nuclear workers and persons, who were exposed to ionizing radiation (IR) due to Chernobyl NPP accident (Romanenko A. et al., 2008). Some clinical features were also indicated, such as: younger age, more advanced symptoms at the onset of disease, more aggressive course with rapid progression, poor response to standard chemotherapy (Klymenko V. et al., 1999, Kryachok I. et al., 2005). The p53 signaling pathway plays an important role in the biology of CLL. Inactivating alterations of TP53 gene by mutation or deletion is strongly associated with adverse clinical outcome and drug resistance. Some single nucleotide polymorphisms (SNP), in particular SNP within TP53 gene at codon 72 (Arg/Pro) and p21 at codon 31 (Ser/Arg) were recently reported may affect p53 pathway function, and influence clinical outcome of CLL. In our study we focused on investigation of these functional SNPs.

TP53 SNP at codon 72 and p21SNP at codon 31 were investigated in 79 IR exposed CLL patients, 76 IR non-exposed CLL patients and 72 controls. CLL patients and control group were compared by gender and age, and two of CLL groups were also compared by clinical data at diagnosis. Genotyping was done using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method according to Hiroshi H. et al., 2007. The digested products were separated on a 3% agarose gel and analyzed.

The both of studied SNPs were in Hardy-Weinberg equilibrium in all groups. The distribution of TP53 genotypes in IR-exposed CLL patients (Arg/Arg 49.4%; Arg/Pro 38%; Pro/Pro 12.6%) did not differ significantly from the distribution in IR non-exposed CLL cohorts (Arg/Arg 44.7%; Arg/Pro 46.1%; Pro/Pro 9.2%; p=0.549) and control group (Arg/Arg 59.9%; Arg/Pro 33.3%; Pro/Pro 6.9%; p=0.201). There were higher frequency of p21 Ser/Arg genotype in IR-exposed CLL patients (Ser/Arg 21.1%; Ser/Ser 78.9%) compared to IR non-exposed CLL (Ser/Arg 8.1%; Ser/Ser 91.9%; p=0.025), but not to controls (Ser/Arg 13.9%; Ser/Ser 86.1%; p=0.453).

We analyzed the association of studied genotypes with some characteristics of CLL patients such as: clinical data at the time of diagnosis (stage, initial white blood cell count, size of lymph nodes), time-to-treatment (TTT), response to treatment, overall survival (OS), progression-free survival (PFS), development of autoimmune complications, secondary tumors, Richter transformation, and immunoglobulin heavy chain variable (IGHV) gene mutation status. Some associations were revealed. Namely, patients with p21 Ser/Arg genotype compared to patients with Ser/Ser genotype had: significantly shorter TTT period (5 mo vs 18 mo; p=0.039), especially in IGHV mutated group (1 mo vs 12 mo; p=0.022), tendency to bulky disease (13.6% vs 5.5%; p=0.16), B-symptoms at diagnosis (22.7% vs 11.8%; p=0.116) and lower frequency of secondary tumors development (4.5% vs 20.5%; p=0.073). Among patients with unmutated IGHV genes TP53 Pro/Pro carriers had shorter PFS (35 mo vs 108 mo; p=0.05) compared to Arg/Arg and Arg/Pro carriers. In summary, we revealed increased number of p21 codon 31 Ser/Arg carriers among IR-exposed CLL patients in comparison with IR non-exposed CLL patients. Further studies are required to evaluate possible role of p21 SNP in development of CLL under IR influence.