TP53 Amplification, a Rare but Recurrent Alteration in Myeloid Neoplasms.
Source: PubMed, NCBI / U.S. National Library of Medicine
The tumor suppressor gene TP53 is a key regulator of genomic stability, frequently altered across human cancers. In hematologic malignancies, TP53 lesions-typically mutations, deletions, and copy-neutral loss of heterozygosity-are associated with complex karyotypes, therapy resistance, and dismal prognosis. Amplifications of TP53, however, have not been systematically described in this context. We retrospectively analyzed cases submitted to our laboratory (09/2005-10/2025) by interphase FISH in which we suspected a TP53 amplification. Among these, eight cases exhibited TP53 amplification, all classified as myeloid neoplasms (n = 6 acute myeloid leukemia, AML; n = 2 myelodysplastic neoplasms, MDS). Median patient age was 72 years (range 48-83). Chromosome banding revealed highly complex karyotypes in all cases (4-12 aberrations), including 5q deletions (in 7/8 patients) and -7/7q- (4/8). Targeted sequencing demonstrated concurrent TP53 mutations in all patients (median variant allele frequency 48%, range 18%-91%) with few additional co-mutations. CNV (copy number variation) analysis confirmed focal TP53 copy number gains, but whole-transcriptome sequencing showed only modest TP53 expression increases, indicating that amplification did not translate into overexpression. Clinical data available for four AML cases revealed a median overall survival of 1 month. These findings indicate that TP53 amplification, although rare, constitutes a r
Abstract
The tumor suppressor gene TP53 is a key regulator of genomic stability, frequently altered across human cancers. In hematologic malignancies, TP53 lesions-typically mutations, deletions, and copy-neutral loss of heterozygosity-are associated with complex karyotypes, therapy resistance, and dismal prognosis. Amplifications of TP53, however, have not been systematically described in this context. We retrospectively analyzed cases submitted to our laboratory (09/2005-10/2025) by interphase FISH in which we suspected a TP53 amplification. Among these, eight cases exhibited TP53 amplification, all classified as myeloid neoplasms (n = 6 acute myeloid leukemia, AML; n = 2 myelodysplastic neoplasms, MDS). Median patient age was 72 years (range 48-83). Chromosome banding revealed highly complex karyotypes in all cases (4-12 aberrations), including 5q deletions (in 7/8 patients) and -7/7q- (4/8). Targeted sequencing demonstrated concurrent TP53 mutations in all patients (median variant allele frequency 48%, range 18%-91%) with few additional co-mutations. CNV (copy number variation) analysis confirmed focal TP53 copy number gains, but whole-transcriptome sequencing showed only modest TP53 expression increases, indicating that amplification did not translate into overexpression. Clinical data available for four AML cases revealed a median overall survival of 1 month. These findings indicate that TP53 amplification, although rare, constitutes a recurrent event in myeloid neoplasms, uniformly accompanied by TP53 mutation and complex cytogenetics. The combination of mutation and amplification likely confers biallelic TP53 inactivation, aligning these cases with multi-hit TP53 AML/MDS characterized by extreme genomic instability and highly adverse outcomes. Taken together, these data indicate that TP53 copy number assessment may be of potential diagnostic interest, although its role in risk stratification requires further studies.