Impact of Low-Burden TP53 Mutations in the Management of CLL

Lazarian, Grégory; Cymbalista, Florence; Baran‐Marszak, Fanny

doi:10.3389/fonc.2022.841630

Cited by 4 publications

(4 citation statements)

References 42 publications

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“…It is becoming apparent that these seemingly contrasting findings are largely influenced by the different patient cohort composition, immunogenetic characteristics i.e. the IGHV status, and the types of therapies applied [ 27 ]. Considering both TP53 and IGHV status we demonstrated significant differences between patients harbouring wild‐type TP53 with unmutated and mutated IGHV.…”

Section: Discussionmentioning

confidence: 99%

Low‐burden TP53 mutations represent frequent genetic events in CLL with an increased risk for treatment initiation

László,

Kotmayer,

Fésüs

et al. 2023

The Journal of Pathology CR

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TP53 aberrations predict chemoresistance and represent a contraindication for the use of standard chemoimmunotherapy in chronic lymphocytic leukaemia (CLL). Recent next‐generation sequencing (NGS)‐based studies have identified frequent low‐burden TP53 mutations with variant allele frequencies below 10%, but the clinical impact of these low‐burden TP53 mutations is still a matter of debate. In this study, we aimed to scrutinise the subclonal architecture and clinical impact of TP53 mutations using a sensitive, NGS‐based mutation analysis in a ‘real‐world’ cohort of 901 patients with CLL. In total, 225 TP53 mutations were identified in 17.5% (158/901) of the patients; 48% of these alterations represented high‐burden mutations, while 52% were low‐burden TP53 mutations. Low‐burden mutations as sole alterations were identified in 39% (62/158) of all mutated cases with 82% (51/62) of these being represented by a single low‐burden TP53 mutation. Patients harbouring low‐burden TP53 mutations had significantly lower time to first treatment compared to patients with wild‐type TP53. Our study has expanded the knowledge on the frequency, clonal architecture, and clinical impact of low‐burden TP53 mutations. By demonstrating that patients with sole low‐burden TP53 variants represent more than one‐third of patients with TP53 mutations and have an increased risk for treatment initiation, our findings strengthen the need to redefine the threshold of TP53 variant reporting to below 10% in the routine diagnostic setting.

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Section: Discussionmentioning

confidence: 99%

Low‐burden TP53 mutations represent frequent genetic events in CLL with an increased risk for treatment initiation

László,

Kotmayer,

Fésüs

et al. 2023

The Journal of Pathology CR

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“…The present work shows that this value did not lead to the inclusion of spurious variants with no impact on TP53 activity, as variants expressed by the above-mentioned minor clones are similar to those found in larger clones with analogous hotspot variant distribution. Moreover, considering the deleterious effect of chemoimmunotherapy in TP53-mutated cases and the availability of Btk inhibitors, it seems adequate to consider patients harboring small TP53-mutated variants as candidates for targeted therapies [17].…”

Section: Discussionmentioning

confidence: 99%

“…Second, concerning TP53, it has shed light on new features such as the occurrence of minor clones, which had remained undetectable by conventional Sanger sequencing [6,[12][13][14][15][16]. The clinical value of these minor clones is still under investigation [17]. In a previous study, using a dataset of 336 TP53-mutated CLL patients, we uncovered a novel TP53 mutation hotspot in codon 234 associated with chlorambucil treatment [18].…”

Section: Introductionmentioning

confidence: 99%

The Broad Spectrum of TP53 Mutations in CLL: Evidence of Multiclonality and Novel Mutation Hotspots

et al. 2023

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TP53 aberrations are a major predictive factor of resistance to chemoimmunotherapy in chronic lymphocytic leukemia (CLL), and an assessment of them before each line of treatment is required for theranostic stratification. Acquisition of subclonal TP53 abnormalities underlies the evolution of CLL. To better characterize the distribution, combination, and impact of TP53 variants in CLL, 1,056 TP53 variants collected from 683 patients included in a multicenter collaborative study in France were analyzed and compared to UMD_CLL, a dataset built from published articles collectively providing 5,173 TP53 variants detected in 3,808 patients. Our analysis confirmed the presence of several CLL-specific hotspot mutations, including a two-base pair deletion in codon 209 and a missense variant at codon 234, the latter being associated with alkylating treatment. Our analysis also identified a novel CLL-specific variant in the splice acceptor signal of intron 6 leading to the use of a cryptic splice site, similarly utilized by TP53 to generate p53psi, a naturally truncated p53 isoform localized in the mitochondria. Examination of both UMD_CLL and several recently released large-scale genomic analyses of CLL patients confirmed that this splice variant is highly enriched in this disease when compared to other cancer types. Using a TP53-specific single-nucleotide polymorphism, we also confirmed that copy-neutral loss of heterozygosity is frequent in CLL. This event can lead to misinterpretation of TP53 status. Unlike other cancers, CLL displayed a high proportion of patients harboring multiple TP53 variants. Using both in silico analysis and single molecule smart sequencing, we demonstrated the coexistence of distinct subclones harboring mutations on distinct alleles. In summary, our study provides a detailed TP53 mutational architecture in CLL and gives insights into how treatments may shape the genetic landscape of CLL patients.

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“…Next‐generation sequencing (NGS) uncovered TP53 mutations below the detection limit of Sanger sequencing, corresponding to a variant allele frequency (VAF) of ~10% 7,8 . Such TP53 micro‐clones often expand during the disease course, positively selected by chemoimmunotherapy (CIT) 9 . Responding to the need for method validation, the European Research Initiative on CLL (ERIC) has invested in offering guidance on TP53 mutation screening, including by NGS, 10 while also running an external quality assessment scheme for laboratories performing the test and holding dedicated educational workshops.…”

Section: Precision Diagnostics and Prognosticationmentioning

confidence: 99%

Realizing precision medicine in chronic lymphocytic leukemia: Remaining challenges and potential opportunities

Stamatopoulos,

Pavlova,

Al‐Sawaf

et al. 2024

HemaSphere

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Patients with chronic lymphocytic leukemia (CLL) exhibit diverse clinical outcomes. An expanding array of genetic tests is now employed to facilitate the identification of patients with high‐risk disease and inform treatment decisions. These tests encompass molecular cytogenetic analysis, focusing on recurrent chromosomal alterations, particularly del(17p). Additionally, sequencing is utilized to identify TP53 mutations and to determine the somatic hypermutation status of the immunoglobulin heavy variable gene. Concurrently, a swift advancement of targeted treatment has led to the implementation of novel strategies for patients with CLL, including kinase and BCL2 inhibitors. This review explores both current and emerging diagnostic tests aimed at identifying high‐risk patients who should benefit from targeted therapies. We outline existing treatment paradigms, emphasizing the importance of matching the right treatment to the right patient beyond genetic stratification, considering the crucial balance between safety and efficacy. We also take into consideration the practical and logistical issues when choosing a management strategy for each individual patient. Furthermore, we delve into the mechanisms underlying therapy resistance and stress the relevance of monitoring measurable residual disease to guide treatment decisions. Finally, we underscore the necessity of aggregating real‐world data, adopting a global perspective, and ensuring patient engagement. Taken together, we argue that precision medicine is not the mere application of precision diagnostics and accessibility of precision therapies in CLL but encompasses various aspects of the patient journey (e.g., lifestyle exposures and comorbidities) and their preferences toward achieving true personalized medicine for patients with CLL.

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Impact of Low-Burden TP53 Mutations in the Management of CLL

Cited by 4 publications

References 42 publications

Low‐burden TP53 mutations represent frequent genetic events in CLL with an increased risk for treatment initiation

Low‐burden TP53 mutations represent frequent genetic events in CLL with an increased risk for treatment initiation

The Broad Spectrum of TP53 Mutations in CLL: Evidence of Multiclonality and Novel Mutation Hotspots

Realizing precision medicine in chronic lymphocytic leukemia: Remaining challenges and potential opportunities

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