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TP53 mutations with low variant allele frequency predict short survival in chronic lymphocytic leukemia
journal contribution
posted on 2023-06-10, 01:27 authored by Riccardo Bomben, Francesca Maria Rossi, Filippo Vit, Tamara Bittolo, Tiziana D'Agaro, Antonella Zucchetto, Erika Tissino, Federico Pozzo, Elena Vendramini, Massimo Degan, Eva Zaina, Ilaria Cattarossi, Paola Varaschin, Paola Nanni, Christopher PepperChristopher Pepper, othersPurpose: In chronic lymphocytic leukemia (CLL), TP53 mutations are associated with reduced survival and resistance to standard chemoimmunotherapy (CIT). Nevertheless, the clinical impact of subclonal TP53 mutations below 10% to 15% variant allele frequency (VAF) remains unclear. Experimental Design: Using a training/validation approach, we retrospectively analyzed the clinical and biological features of TP53 mutations above (high-VAF) or below (low-VAF) the previously reported 10.0% VAF threshold, as determined by deep next-generation sequencing. Clinical impact of low-VAF TP53 mutations was also confirmed in a cohort (n = 251) of CLL treated with fludarabine-cyclophosphamide-rituximab (FCR) or FCR-like regimens from two UK trials. Results: In the training cohort, 97 of 684 patients bore 152 TP53 mutations, while in the validation cohort, 71 of 536 patients had 109 TP53 mutations. In both cohorts, patients with the TP53 mutation experienced significantly shorter overall survival (OS) than TP53 wild-type patients, regardless of the TP53 mutation VAF. By combining TP53 mutation and 17p13.1 deletion (del17p) data in the total cohort (n = 1,220), 113 cases were TP53 mutated only (73/113 with low-VAF mutations), 55 del17p/TP53 mutated (3/55 with low-VAF mutations), 20 del17p only, and 1,032 (84.6%) TP53 wild-type. A model including low-VAF cases outperformed the canonical model, which considered only high-VAF cases (c-indices 0.643 vs. 0.603, P < 0.0001), and improved the prognostic risk stratification of CLL International Prognostic Index. Clinical results were confirmed in CIT-treated cases (n = 552) from the retrospective cohort, and the UK trials cohort. Conclusions: TP53 mutations affected OS regardless of VAF. This finding can be used to update the definition of TP53 mutated CLL for clinical purposes.
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Publication status
- Published
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- Accepted version
Journal
Clinical Cancer ResearchISSN
1078-0432Publisher
American Association for Cancer ResearchExternal DOI
Issue
20Volume
27Page range
5566-5575Event location
United StatesDepartment affiliated with
- Clinical and Experimental Medicine Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2021-10-21First Open Access (FOA) Date
2022-07-21First Compliant Deposit (FCD) Date
2021-10-21Usage metrics
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