Abstract
In chronic lymphocytic leukemia (CLL), the worst prognosis is associated with TP53 defects with the affected patients being potentially directed to alternative treatment. Therapy administration was shown to drive the selection of new TP53 mutations in CLL. Using ultra-deep next-generation sequencing (NGS), we performed a detailed analysis of TP53 mutations' clonal evolution. We retrospectively analyzed samples that were assessed as TP53-wild-type (wt) by FASAY from 20 patients with a new TP53 mutation detected in relapse and 40 patients remaining TP53-wt in relapse. Minor TP53-mutated subclones were disclosed in 18/20 patients experiencing later mutation selection, while only one minor-clone mutation was observed in those patients remaining TP53-wt (n=40). We documented that (i) minor TP53 mutations may be present before therapy and may occur in any relapse; (ii) the majority of TP53-mutated minor clones expand to dominant clone under the selective pressure of chemotherapy, while persistence of minor-clone mutations is rare; (iii) multiple minor-clone TP53 mutations are common and may simultaneously expand. In conclusion, patients with minor-clone TP53 mutations carry a high risk of mutation selection by therapy. Deep sequencing can shift TP53 mutation identification to a period before therapy administration, which might be of particular importance for clinical trials.
Highlights
In chronic lymphocytic leukemia (CLL), patients harboring TP53 defects represent a major challenge concerning the effective treatment.[1]
next-generation sequencing (NGS) analysis reveals the presence of minor mutated clones before their therapy-driven selection In the first part of our retrospective study, we focused on 20 patients who had acquired a new TP53 mutation in relapse, as Consecutive TP53 mutational analysis confirms the prominent impact of newly acquired TP53 mutations on survival
Among 121 patients who did not receive any therapy during the follow-up, new TP53 mutations were observed in only one patient
Summary
In chronic lymphocytic leukemia (CLL), patients harboring TP53 defects represent a major challenge concerning the effective treatment.[1] TP53 mutation and/or 17p deletion severely impede response to chemotherapy,[2,3] and affected patients manifest short clinical responses to its combination with rituximab.[4,5]. Alemtuzumab is supposed to act independently on p53, the response rates in monotherapy are far from satisfactory in chemorefractory patients.[6] The inability of mutated p53 protein to induce apoptosis properly seems to be a primary reason for the observed resistance to treatment.[7] The p53 dysfunction is the major cause of genomic instability in CLL cells,[8] which leads to the acquisition of other genomic variants available for further selection. The frequency of TP53 defects at diagnosis or before first therapy is only between 5 and 15%,2,3,10,11 but the proportion of affected patients is significantly higher after treatment and has been reported to be as high as 44% in a fludarabine-refractory cohort.[12]
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