Landscape of TP53 Alterations in Chronic Lymphocytic Leukemia via Data Mining Mutation Databases.

Thierry Soussi,Panagiotis Baliakas

doi:10.3389/fonc.2022.808886

Abstract

Locus-specific databases are invaluable tools for both basic and clinical research. The extensive information they contain is gathered from the literature and manually curated by experts. Cancer genome sequencing projects generate an immense amount of data, which are stored directly in large repositories (cancer genome databases). The presence of a TP53 defect (17p deletion and/or TP53 mutations) is an independent prognostic factor in chronic lymphocytic leukemia (CLL) and TP53 status analysis has been adopted in routine clinical practice. For that reason, TP53 mutation databases have become essential for the validation of the plethora of TP53 variants detected in tumor samples. TP53 profiles in CLL are characterized by a great number of subclonal TP53 mutations with low variant allelic frequencies and the presence of multiple minor subclones harboring different TP53 mutations. In this review, we describe the various characteristics of the multiple levels of heterogeneity of TP53 variants in CLL through the analysis of TP53 mutation databases and the utility of their diagnosis in the clinic.

Highlights

In 1956, Ingram used protein sequencing to provide the first demonstration of a severe disease resulting from a single amino acid substitution [1]
Bi-allelic TP53 inactivation could explain two TP53 variants but not a higher number of them [34]. This high intratumor heterogeneity has been detected in multiple independent studies and validated by specific analyses such as FASAY and SMRT that confirm different allelic locations for these TP53 variants
In the early phase of the disease, TP53 mutations appear to be either absent or infrequent, but this issue needs to be carefully reevaluated using NGS assays validated for limits of detection (LOD) ranging from 0.05% to 1% (Figure 4, panel 1). Because these variants are usually not associated with a deletion of the second allele, FISH or single nucleotide polymorphisms (SNPs) arrays are not suitable for early detection analyses (Figure 4, panel 2). 17p deletion and complex karyotypes occur during disease progression, leading to the conventional view of chronic lymphocytic leukemia (CLL) with a single TP53 mutation associated with TP53 loss of heterozygosity (LOH) (Figure 4, panel 3)

Summary

Introduction

In 1956, Ingram used protein sequencing to provide the first demonstration of a severe disease (human sickle-cell anemia in that work) resulting from a single amino acid substitution [1]. Data from two recent large-scale studies analyzing TP53 LOF via multiple assays in mammalian cells have been included in UMD_TP53 to refine TP53 variant classification [17,18,19].

Results

Conclusion