TP53 alterations in acute myeloid leukemia with complex karyotype correlate with specific copy number alterations, monosomal karyotype, and dismal outcome

Abstract

To assess the frequency of TP53 alterations and their correlation with other genetic changes and outcome in acute myeloid leukemia with complex karyotype (CK-AML), we performed integrative analysis using TP53 mutational screening and array-based genomic profiling in 234 CKAMLs. TP53 mutations were found in 141 of 234 (60%) and TP53 losses were identified in 94 of 234 (40%) CK-AMLs; in total, 164 of 234 (70%) cases had TP53 alterations. TP53-altered CK-AML were characterized by a higher degree of genomic complexity (aberrations per case, 14.30 vs 6.16; P < .0001) and by a higher frequency of specific copy number alterations, such as ؊5/5q؊, ؊7/7q؊, ؊16/ 16q؊, ؊18/18q؊, ؉1/؉1p, and ؉11/؉11q/ amp11q13ϳ25; among CK-AMLs, TP53-altered more frequently exhibited a monosomal karyotype (MK). Patients with TP53 alterations were older and had significantly lower complete remission rates, inferior event-free, relapse-free, and overall survival. In multivariable analysis for overall survival, TP53 alterations, white blood cell counts, and age were the only significant factors. In conclusion, TP53 is the most frequently known altered gene in CK-AML. TP53 alterations are associated with older age, genomic complexity, specific DNA copy number alterations, MK, and dismal outcome. In multivariable analysis, TP53 alteration is the most important prognostic factor in CK-AML, outweighing all other variables, including the MK category. (Blood. 2012;119(9):2114-2121)

Monosomal Karyotypes among 1147 Chinese Patients with Acute Myeloid Leukemia: Prevalence, Features and Prognostic Impact

“…On the other hand, there was little insight into the mechanism of MK contributing to dismal prognosis. Some studies implicated that MK in AML associated with high functional multidrug resistance activity or TP53 alterations (Ahn et al, 2012;Rücker et al, 2012). However, these observations need to be further investigated.…”

High p53 protein expression in therapy-related myeloid neoplasms is associated with adverse karyotype and poor outcome

“…3,13,15,19 TP53 mutations are often associated with loss of heterozygosity of the TP53 locus and cytogenetic defects such as À 5/del(5q) and 17p-. 3,9,13,[19][20][21] The importance of TP53 mutations has been validated in myelodysplastic syndrome in the non-therapy-related setting, particularly in myelodysplastic syndrome with del(5q). 21,22 One recent study showed that TP53 mutations in therapyrelated myeloid neoplasms predicted an inferior clinical outcome compared with wild-type TP53, but the authors examined a relatively small number of cases.…”

Chromothripsis is linked to TP53 alteration, cell cycle impairment, and dismal outcome in acute myeloid leukemia with complex karyotype

“…[2][3][4] In AML, TP53 alterations (loss and/or mutation) are almost exclusively found in cases with complex karyotype (CK) AML and define a subset of patients with distinct genomic alterations and dismal outcome. 5,6 To gain further insight into the role of chromothripsis in AML, we performed an integrative analysis consisting of genomic profiling (Affymetrix GeneChip Human Mapping 250K Array (n=61), Genome-Wide Human SNP Array 6.0 profiling (n=51) [GEO accession number GSE 34542]) and TP53 mutation screening in 112 CK-AML patients. 5,7 The findings were correlated with clinical and genetic data of all CK-AML, whereas outcome analysis was restricted to 62 patients treated with intensive chemotherapy.…”