期刊
CLINICAL CANCER RESEARCH
卷 27, 期 20, 页码 5566-5575出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-21-0701
关键词
-
类别
资金
- Progetto Ricerca Finalizzata [PE-2016-02362756, RF-2018-12365790]
- Italian Ministry of Health, Rome, Italy
- Associazione Italiana Ricerca Cancro (AIRC) [IG-21687]
- Associazione Italiana contro le Leucemie, linfomi e mielomi (AIL), Venezia Section, Pramaggiore/Veneto Orientale Group, Italy [LR 17/2014]
- 5 x 1000 Intramural Program, Centro di Riferimento Oncologico, Aviano, Italy
- Fondazione Umberto Veronesi
- Italian Ministry of Health 5 X 1000 funds
- Compagnia S. Paolo Turin Italy project [2017.0526]
- Blood Cancer UK [18005]
This study retrospectively analyzed the clinical impact of TP53 mutations in chronic lymphocytic leukemia, finding that TP53 mutations affect overall survival regardless of variant allele frequency. The results of the study suggest updating the definition of TP53 mutated CLL for clinical purposes.
Purpose: 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 nextgeneration 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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据