Pro72 Allele Potentially Increases the Poor Prognostic Value of p53 Mutations In Chinese Patients with Chronic Lymphocytic Leukemia.
Authors: Dong Huajie , Fang Cheng , Fan Lei , Zhu Danxia , Wang Dongmei , Zhu Huayuan , Zhuang Yun , Miao Kourong , Liu Peng , Xu Wei , Li Jianyong 
Published: October 2019

Abstract
Abstract 4612

Background:
The poor prognosis of chronic lymphocytic leukemia (CLL) patients with del(17p13) is well established. Association of p53 mutations and its codon 72 polymorphism with CLL prognosis has been studied. However, there is no study on p53 mutations in Chinese patients with CLL to date, and the joint effect of p53 mutations and p53 codon 72 polymorphism on the prognosis of CLL remains uncertain.

Methods:
The frequency of p53 codon 72 genotype and the p53 mutations status were assessed by direct sequencing and correlated with clinical outcome in 180 CLL patients. p53 deletions of 168 patients were detected by interphase fluorescence in situ hybridization (FISH).

Results:
1. p53 mutations were detected in 17.8% (32/180) of samples. Most patients with del(17p13) had p53 mutations (73.7%; 14/19) and mutations in the absence of del(17p13) were found in 10.7% (18/168) in our cohort, which were much higher than other countries. The frequencies of p53 Arg72Pro genotypes were similar across the control (Arg/Arg: 29.6%; Arg/Pro: 50.5%; Pro/Pro: 19.9%) and patient groups (Arg/Arg: 28.3%; Arg/Pro: 45.6%; Pro/Pro: 26.1%). 2. Compared with cases without p53 mutations, p53 mutations were associated with advanced stages (P<0.001), unmutated immunoglobulin heavy-chain variable region (IGHV) status (P=0.016) and chemorefractoriness (P<0.001). The Pro/Pro genotype was associated with an increased incidence of p53 mutations (P=0.003) and deletions (P=0.02) but did not appear to influence other biological behavior or clinical response. Compared to the cases with p53 wild-type, patients with p53 mutations and Pro72 allele (Arg/Pro + Pro/Pro genotypes) were associated with advanced stages (P=0.002) and chemorefractoriness (P<0.001) but not with p53 mutations and Arg/Arg. 3. Survival analysis showed that the occurrence of p53 mutations and del(17p13) were associated with shorter overall survival (OS). Mean OS for patients with p53 mutations was 83.2 months (95% CI, 61.6–104.8 months), whereas mean OS for patients without p53 mutations was 148.8 months (95% CI, 134.5–163.1 months) (P <0.001). Mean OS for patients with del(17p13) was 58.7 months (95% CI, 39.1–78.4 months) versus 142.5 months (95% CI, 128.2–156.9 months) for patients devoid of del(17p13) (P<0.001). Binet stages B+C (P=0.026), p53 deletions (P=0.01), and p53 mutations (P=0.014) were the variables strongly associated with OS by multivariate Cox regression analysis. The p53 codon 72 polymorphisms did not influence OS in the entire patient group. But there was significant difference in OS among p53 mutations with Arg/Arg homozygotes and Pro72 allele (P=0.046). When patients with p53 wild-type and p53 codon 72 Arg/Arg genotype were selected as a reference (HR = 1.00), patients with p53 mutation and p53 codon 72 Arg/Arg genotype did not show a significant increase in HR for OS (HR = 1.82; 95% CI 0.16–20.13; P = 0.628). Notably, patients with both p53 mutation and p53 codon 72 Pro72 allele experienced a 10.5-fold HR for OS (95% CI 2.13–51.8; P = 0.004). Similarly, there was statistically significant influence on OS among p53 mutation and p53 codon 72 Pro/Pro genotype (HR = 7.73; 95% CI 1.39–43.03; P = 0.02). 4. We also found that cases with p53 mutations in the absence of del(17p13) had a similar clinical and biological course and similar poor short OS as cases carrying del(17p13) in Chinese population. Compared with CLL without p53 disruptions, cases harboring del(17p13) or isolated p53 mutations, uniformly displayed an unmutated IGHV status (P=0.014), Binet stages B+C (P=0.003) and chemorefractoriness (P=0.009). Survival analysis also showed that the patients with isolated p53 mutations had significantly shorter OS (mean, 95.3 months) (95% CI, 72.3–118.3 months) than the patients without p53 disruptions (P=0.014).

Conclusion:
Our study showed that cases with p53 mutations and p53 mutations without del(17p13) may be adverse prognostic factors in Chinese CLL cohort. Moreover, p53 Pro72 allele potentially increases the prognostic value of p53 mutations in CLL.

Disclosures:
No relevant conflicts of interest to declare.