The prognostic impact of variant allele frequency (VAF) in TP53 mutant patients with MDS: A systematic review and meta‐analysis

Abstract

Tumor protein p53 (TP53) is frequently expressed in patients with myelodysplastic syndromes (MDS). Studies have already reported the poor prognostic impact of TP53 gene mutations in MDS patients. However, parts of this subgroup of patients with low-risk MDS still have relatively better survival and longer remission times. Therefore, we performed a meta-analysis to evaluate the prognostic difference intragene of variant allele frequency (VAF). The primary endpoint was overall survival (OS), and event-free survival (EFS) was selected as the secondary endpoint. We extracted the hazard ratio (HR) and 95% confidence interval (CI) for OS and EFS from univariate and multivariate Cox proportional hazard models. A total of 4003 MDS patients and 1278 TP53-mutated patients from 13 cohorts of 11 studies up to February 24, 2020, were included in our meta-analysis. Pooled HRs suggested that a high mutant VAF had an adverse impact on OS (HR = 2.11, 95% CI: 1.48-3.01, P < .0001) but no impact on EFS (HR = 15.57, 95% CI: 0.75-324.44, P = .003) in MDS patients. Twenty percent is a proper threshold to set (HR = 2.02, 95% CI: 1.31-3.13, P = .001) and is a rough line between high clone burden and low clone burden, while 40% is an exact cutoff point (HR = 2.11, 95% CI: 1.26-3.55, P < .0001) to guide diagnosis and treatment. Beyond the traditional binary classification of gene mutation, we aimed to find a way to divide mutant molecular markers more specifically by VAF to provide clinical therapeutic values. Our meta-analysis indicates that a high VAF is an independent, adverse prognostic factor for OS in TP53 mutant MDS patients. Patients with mediate/low-frequency parts who could be treated like wide-type patients have relatively better survival and may choose allogeneic hematopoietic stem cell transplantation as conditions permitting. Further prospective studies are needed in the future, and a large subgroup analysis of the same cutoff point subgroups is needed to obtain a more reliable basis for the impact of other mutant gene VAFs on the prognosis of MDS.

Comparison of acute myeloid leukemia and myelodysplastic syndromes with TP53 aberrations

“…In contrast, in AML patients treated non-intensively with the hypomethylating drug azacitidine, an increasing mutant TP53 load was associated with a significantly increased risk for treatment failure [ 34 ]. A systematic review and meta-analysis of studies of patients with MDS also reported a high TP53 VAF as an independent prognostic parameter for survival with a 40% VAF as cutoff for high and low clonal burdens [ 35 ]. Recently, a report focusing on large cohorts of patients with MDS implemented the “ TP53 allelic state” as an important biological and clinical parameter.…”

Exome sequencing can misread high variant allele fraction of somatic variants in UBA1 as hemizygous in VEXAS syndrome: a case report

“…Interestingly, due to the high VAF, the UBA1 pathogenic variant in our case was misinterpreted as being in a hemizygous state. High VAF has been described in the literature to occur in postzygotic event such as clonal hematopoiesis in variants in TP53 with median VAF of 67.7% (range 46.9–84.7%) [ 17 ]. Regarding VEXAS, the highest value described in the literature was 83.35% in a patient diagnosed after analysis of peripheral-blood ES data [ 13 ].…”

TP53 in Myelodysplastic Syndromes

“…The treatment of lenalidomide in MDS patients with isolated del(5q) harboring TP53 mutations is at a high risk of treatment failure and disease progression; this heterogeneity caused by TP53 mutations may significantly affect clinical decision making for MDS-del(5q) [ 56 ]. The genomic instability caused by TP53 inactivation was considered the pivotal reason for the accumulated chromosomal rearrangements [ 38 , 57 ], and the karyotype complexity is highly related to the variant allele frequency (VAF) of TP53 [ 58 ], which is an independent adverse prognostic factor for OS in MDS patients with TP53 mutations [ 59 ].…”