TP53 alterations in relapsed childhood acute lymphoblastic leukemia

Abstract

TP53 alterations are frequent relapse‐acquired mutations in childhood acute lymphoblastic leukemia (ALL). The present study evaluated the clinical significance of relapsed childhood ALL in Taiwan. Diagnostic and/or relapsed bone marrow or peripheral blood was obtained from 111 children with relapsed ALL who were initially treated by using Taiwan Pediatric Oncology Group (TPOG) ALL protocols from January 1997 to May 2018. Mutations were detected by PCR and sequencing, as well as by multiplex ligation‐dependent probe amplification to detect copy number alterations. Copy number and/or sequence alterations of TP53 were detected in 29% (28 of 98) and in 46% (6 of 13) of patients with relapsed B‐cell and T‐cell ALL, respectively. This incidence was much higher than that in several similar studies conducted in Caucasian populations. Seventy percent of all TP53 alterations were gained at relapse in 67 matched samples by back‐tracking matched diagnostic samples. TP53 alterations were associated with lower 5‐year event‐free survival (EFS) and overall survival (OS) rates (P = .013 and P = .0002, respectively). Multivariate analysis confirmed the prognostic significance of TP53 alterations. Forty‐five patients received hematopoietic stem‐cell transplantations post‐relapse. Patients with TP53 alterations (14/45) had inferior 5‐year EFS and OS than patients without TP53 alterations after transplantation (P = .002 and P = .001, respectively). The significance of these TP53 alterations for patients who received transplantations was confirmed by multivariate analysis. In conclusion, TP53 alterations were enriched and useful as prognostic markers in relapsed childhood ALL.

Targeted sequencing to identify genetic alterations and prognostic markers in pediatric T-cell acute lymphoblastic leukemia

“…In addition, we had ten patients with paired diagnostic and relapsed samples. One of the notable findings in our study was that four patients had acquired TP53 mutations, which is compatible with our previous study 53 .…”

Integrated Genomic Analysis of Chromosomal Alterations and Mutations in B-Cell Acute Lymphoblastic Leukemia Reveals Distinct Genetic Profiles at Relapse

“…In this study, TP53 is the most frequently mutated gene at relapse (31%). TP53 abnormalities (deletion and/or mutation) have been associated with a resistance to treatment and worse prognosis in childhood and adult ALL [8,33]. TP53 gene abnormalities have a key role in ALL relapse, as they independently predict a high risk of treatment failure in ALL patients [8,24,34].…”

“…TP53 abnormalities (deletion and/or mutation) have been associated with a resistance to treatment and worse prognosis in childhood and adult ALL [ 8 , 33 ]. TP53 gene abnormalities have a key role in ALL relapse, as they independently predict a high risk of treatment failure in ALL patients [ 8 , 24 , 34 ]. The presence of TP53 alterations has been associated with a reduced response rate to induction therapy and correlated with a shortened duration of survival, even after successful reinduction therapy [ 35 , 36 ].…”

“…It is well known that relapsed ALL is a heterogeneous disease and that distinct genetic alterations may be unique to small subgroups of patients [3]. Genomic studies of matched diagnosis-relapse samples from ALL patients have shed light on the clonal evolution that leads to relapse, the pathways associated with chemoresistance, and the potential targets for therapy [4][5][6][7][8][9]. However, the mechanisms that probably fuel an ALL relapse are not fully understood.…”

MLPA and DNA index improve the molecular diagnosis of childhood B-cell acute lymphoblastic leukemia

“…The DNA pellet was washed with 75% ethanol and rehydrated with Tris-EDTA buffer. The concentration of DNA was determined using a NanoDrop 1,000 spectrophotometer (Thermo Fisher Scientific, Waltham, Massachusetts, USA) 32 .…”