PhD Scientific Days 2022

Pathology and Oncology III. (Poster discussion will take place in the Aula during the Coffee Break)

Investigation of TP53 Mutations in Chronic Lymphocytic Leukemia Using Next Generation Sequencing

Text of the abstract

Introduction: TP53 aberrations (TP53 mutations and/or deletions of the chromosomal region 17p) are associated with chemoresistance, hence represent a contraindication for use of standard chemoimmunotherapy in chronic lymphocytic leukemia (CLL). Subclonal (low-burden) TP53 mutations represent a subpopulation of the tumor cells, with variant allele frequencies (VAF) below the 10% threshold. Clinical impact of these sublclonal variants is still the subject of extensive study, with some results suggesting the same unfavourable prognostic impact as in the case of clonal alterations.
Aims: In our study, we aimed to explore the subclonal architecture and the clinical impact of low-burden TP53 mutations in a Hungarian ”real-world” cohort.
Method: Peripherial blood samples were collected from 509 CLL patients from 11 Hungarian oncohematological centres. TP53 mutations were detected using targeted next-generation sequencing. Kaplan-Meier-survival curves and log rank tests were performed to compare survival times between different groups.
Results: We identified 224 TP53 mutations in 25% (127/509) of the patients. High-burden (>10% VAF) mutations represented 39% (n=88) of these alterations, while 61% (n=136) of the TP53 mutations were low-burden. Subclonal mutations as sole alterations were identified in 38% (48/127) of all mutated cases. In 33% of the TP53 mutant cases, we detected multiple mutations with heterogenous sublclonal architecture. In the subcohort of patients treated with chemoimmunotherapy without the implication of targeted agents (n=200), patients with TP53 mutation (n=31) had significantly lower overall survival (OS) as compared to the patients with wild type (n=169) TP53 gene (p=0,009). No significant differences were detected in the OS between patients with low-burden TP53 mutations and wild type cases.
Conclusion: In this study we explored the clonal architecture and clinical impact of low burden TP53 mutations in a nation-wide, “real world” Hungarian patient cohort. Our results demonstrate that patients with sole low-burden TP53 mutations represent more than one third of patients with TP53 aberration, hence the 10% cut-off value might worth reconsidering for TP53 variant reporting in routine diagnostics.
Funding:Horizon2020 739593, K21_137948, FK20_134253, TKP2021-EGA-24 and TKP2021-NVA-15, the EFOP-3.6.3-VEKOP-16-2017-00009 and ÚNKP-21-2-I-SE-21.