Detailed Analysis of Treatment-related Clonal Evolution in CLL Through the Identification of Abnormal Molecular Pathways

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F65269705%3A_____%2F21%3A00075065" target="_blank" >RIV/65269705:_____/21:00075065 - isvavai.cz</a>

Výsledek na webu

<a href="https://www.tandfonline.com/doi/abs/10.1080/10428194.2021.1995175" target="_blank" >https://www.tandfonline.com/doi/abs/10.1080/10428194.2021.1995175</a>

DOI - Digital Object Identifier

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Jazyk výsledku

angličtina

Název v původním jazyce

Detailed Analysis of Treatment-related Clonal Evolution in CLL Through the Identification of Abnormal Molecular Pathways

Popis výsledku v původním jazyce

Introduction: In chronic lymphocytic leukemia (CLL), an acquisition and clonal expansion of genomic aberrations are reflected in clinical outcomes. CLL with TP53 gene defects represents a major challenge concerning an effective treatment (Stefaniuk, 2021). Chemoimmunotherapy remains a treatment of choice in many countries even in the era of novel agents, however, is associated with the expansion of small subclones bearing mutant TP53 (Rossi et al., 2014; Malcikova et al., 2015). Such an event usually leads to disease course deterioration and therapy resistance. Still, there is a subset of CLL patients harboring TP53-mutated clones with &lt;10% variant allele frequency (VAF) that do not expand even after several therapy lines (Malcikova et al., 2021). The significance of these low-burden mutations remains a matter of interest. We aimed to explore somatic gene variants and to identify molecular genetic factors affecting the ability of TP53-mutated clones to expand. Methods: The study was performed on a retrospective cohort of 53 CLL patients with a well-documented clinical course and different scenarios of TP53 mutation expansion (i.e. 27 patients with TP53 mutations expanding in disease relapse, 21 patients with stable low-burden TP53 mutations, and five patients keeping wild-type TP53 throughout the disease course as a control). Our cohort included patients treated with standard chemoimmunotherapy, but also with bcl-2 and BCR-signaling inhibitors. TP53 mutational status was tested using ultra-deep NGS of exons 2-11. Tumor samples from various stages of CLL were investigated using whole-exome sequencing. Using our recently published approach (Taus et al., 2021) abnormal molecular pathways were extracted. Differently mutated pathways and co-occurring or mutually exclusive mutations were identified in defined patient groups. Results: We investigated 2-5 subsequent tumor samples from each patient with a median interval between the first and last sample of 70 months. We compared mutation profiles in different stages of the disease. In addition to recurrent mutations in known CLL-associated genes, such as SF3B1, ATM, NOTCH1, BIRC3, or NFKBIE, we identified many unique mutations that emerged or diminished under the treatment pressure. We inspected how their increase or elimination correlated with the clonal development of TP53 mutations. We found that the presence of driver mutations in CLL-associated genes prevents the expansion of TP53 mutated clones at the early stages of CLL. We observed the mutual exclusivity of mutations in TP53 and ATM, which are both involved in the cell cycle control and DNA-damage response. On the other hand, statistically significant co-occurrence was observed, e.g. for SETD2 involved in the chromatin modification and FBXW7 belonging to the Notch signaling. In the groups of patients with different clinical outcomes and TP53 mutation evolution, we observed distinct sets of mutated genes and affected pathways. Among the aberrant pathways, we identified those recurrently affected by mutations in CLL (e.g. DNA-damage response, Notch, and NF-kB signaling), and, strikingly, also the processes deregulated commonly in CLL but without previously described recurrently mutated components (e.g. adipogenesis or oxidative phosphorylation). Conclusion: We identified changes in the clonal composition of somatic mutations during the CLL disease course and assessed molecular pathways affected by gene mutations. Some mutations occurred concurrently, while others were mutually exclusive, emphasizing the theory that mutations in genes belonging to the same molecular pathway typically do not occur together, most likely due to the lethal effect on a cell. Our results contribute to the understanding of the molecular grounds of CLL clonal evolution, which is necessary for the rational use of available treatment options.

Název v anglickém jazyce

Detailed Analysis of Treatment-related Clonal Evolution in CLL Through the Identification of Abnormal Molecular Pathways

Popis výsledku anglicky

Introduction: In chronic lymphocytic leukemia (CLL), an acquisition and clonal expansion of genomic aberrations are reflected in clinical outcomes. CLL with TP53 gene defects represents a major challenge concerning an effective treatment (Stefaniuk, 2021). Chemoimmunotherapy remains a treatment of choice in many countries even in the era of novel agents, however, is associated with the expansion of small subclones bearing mutant TP53 (Rossi et al., 2014; Malcikova et al., 2015). Such an event usually leads to disease course deterioration and therapy resistance. Still, there is a subset of CLL patients harboring TP53-mutated clones with &lt;10% variant allele frequency (VAF) that do not expand even after several therapy lines (Malcikova et al., 2021). The significance of these low-burden mutations remains a matter of interest. We aimed to explore somatic gene variants and to identify molecular genetic factors affecting the ability of TP53-mutated clones to expand. Methods: The study was performed on a retrospective cohort of 53 CLL patients with a well-documented clinical course and different scenarios of TP53 mutation expansion (i.e. 27 patients with TP53 mutations expanding in disease relapse, 21 patients with stable low-burden TP53 mutations, and five patients keeping wild-type TP53 throughout the disease course as a control). Our cohort included patients treated with standard chemoimmunotherapy, but also with bcl-2 and BCR-signaling inhibitors. TP53 mutational status was tested using ultra-deep NGS of exons 2-11. Tumor samples from various stages of CLL were investigated using whole-exome sequencing. Using our recently published approach (Taus et al., 2021) abnormal molecular pathways were extracted. Differently mutated pathways and co-occurring or mutually exclusive mutations were identified in defined patient groups. Results: We investigated 2-5 subsequent tumor samples from each patient with a median interval between the first and last sample of 70 months. We compared mutation profiles in different stages of the disease. In addition to recurrent mutations in known CLL-associated genes, such as SF3B1, ATM, NOTCH1, BIRC3, or NFKBIE, we identified many unique mutations that emerged or diminished under the treatment pressure. We inspected how their increase or elimination correlated with the clonal development of TP53 mutations. We found that the presence of driver mutations in CLL-associated genes prevents the expansion of TP53 mutated clones at the early stages of CLL. We observed the mutual exclusivity of mutations in TP53 and ATM, which are both involved in the cell cycle control and DNA-damage response. On the other hand, statistically significant co-occurrence was observed, e.g. for SETD2 involved in the chromatin modification and FBXW7 belonging to the Notch signaling. In the groups of patients with different clinical outcomes and TP53 mutation evolution, we observed distinct sets of mutated genes and affected pathways. Among the aberrant pathways, we identified those recurrently affected by mutations in CLL (e.g. DNA-damage response, Notch, and NF-kB signaling), and, strikingly, also the processes deregulated commonly in CLL but without previously described recurrently mutated components (e.g. adipogenesis or oxidative phosphorylation). Conclusion: We identified changes in the clonal composition of somatic mutations during the CLL disease course and assessed molecular pathways affected by gene mutations. Some mutations occurred concurrently, while others were mutually exclusive, emphasizing the theory that mutations in genes belonging to the same molecular pathway typically do not occur together, most likely due to the lethal effect on a cell. Our results contribute to the understanding of the molecular grounds of CLL clonal evolution, which is necessary for the rational use of available treatment options.

Druh

O - Ostatní výsledky

CEP obor

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OECD FORD obor

30204 - Oncology

Projekt

<a href="/cs/project/NU21-08-00237" target="_blank" >NU21-08-00237: Pokročilé sekvenační metody pro analýzu strukturních přestaveb nádorového genomu</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)<br>I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2021

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů