The TP53 Codon72 Polymorphism Is Associated with TP53 Mutations in Chronic Lymphocytic Leukemia

Abstract 1783

TP53 is one of the most important cell-cycle regulator genes and its tumor suppressor activity is fundamental in cellular responses. Mutations in TP53 are known to influence clinical outcome in diverse diseases. In particular, a relationship between TP53 mutations and a poor prognosis has been established in chronic lymphocytic leukemia (CLL), which is one of the most commonly diagnosed lymphoid malignancies in Western countries. Thus far, it has been demonstrated that TP53 mutations are associated with codon72 polymorphism in different diseases e.g. breast cancer, lung cancer, head and neck squamous cell carcinoma, and that this variant could determine cancer susceptibility. In this study, we investigated the overall TP53 mutation rate in 511 CLL and focused on the codon72 polymorphism (rs1042522) in exon 4 (transcript-ID: ENST00000269305). We initially examined the published available 1000 Genome Project results of the European cohort: from a total of 283 genomes analyzed, 137 showed an ARG/ARG genotype (48%), 124 an ARG/PRO genotype (43%) and 22 a PRO/PRO genotype (7.7%). Secondly, in order to determine a potential association between this polymorphic variant and mutations in the TP53 gene, we investigated 511 thoroughly characterized patients with CLL, all diagnosed by immunophenotyping in our laboratory. For molecular analyses, all cases were analyzed for TP53 mutations (exon 4 to exon 11) either by DHPLC and subsequent Sanger sequencing (n=210/511), or using a sensitive next-generation amplicon deep-sequencing assay (n=301/511) (454 Life Sciences, Branford, CT). We observed the occurrence of the three distinct genotypes (ARG/ARG, ARG/PRO, PRO/PRO) of codon72 in the CLL cohort and detected ARG/ARG as the most common genotype (63%), followed by ARG/PRO (31.7%), and PRO/PRO (5.3%); very similar to the distribution of the codon72 polymorphism in the 1000 Genome Project data. Moreover, mutations in TP53 were detected in 63/511 patients resulting in an overall mutation rate of 12%, which reflects the expected mutation rate in this disease. Importantly, as already demonstrated in other malignancies, we here present that also in CLL patients harboring a PRO/PRO genotype a significantly higher frequency of TP53 mutations (9/27, 33%) was observed compared to ARG/ARG (41/321, 13%, P=.037) and ARG/PRO (13/163, 8%, P=.012). With respect to the clinical outcome we confirmed a generally poor survival for the TP53 mutated cases as compared to TP53 wild-type patients (n=23 vs. 189 with clinical data available, alive at 7 years: 29.6% vs. 88.1%; P<.001). Moreover, the impact of the three distinct genotypes on outcome was analyzed. However, no correlation was detectable, neither in the cohort of TP53 mutated cases (P=.225) nor in the TP53 wild-type patients (P=.190). In summary, we demonstrated a significant association between the codon72 allelic variant and TP53 mutation rate in our CLL cohort. Patients with a PRO/PRO genotype showed a significantly higher frequency of TP53 mutations than all other genotypes. However, no prognostic impact of codon72 allelic variant was observed, neither in the TP53 wild-type nor in the TP53 mutated cohort.