Clinical impact of small TP53 mutated subclones in chronic lymphocytic leukemia

Davide Rossi, Hossein Khiabanian, Valeria Spina, Carmela Ciardullo, Alessio Bruscaggin, Rosella Famà, Silvia Rasi, Sara Monti, Clara Deambrogi, Lorenzo De Paoli, Jiguang Wang, Valter Gattei, Anna Guarini, Robin Foà, Raul Rabadan, Gianluca Gaidano

Research output: Contribution to journalArticle

Abstract

TP53 mutations are strong predictors of poor survival and refractoriness in chronic lymphocytic leukemia (CLL) and have direct implications for disease management. Clinical information on TP53 mutations is limited to lesions represented in >20% leukemic cells. Here, we tested the clinical impact and prediction of chemorefractoriness of very small TP53 mutated subclones. The TP53 gene underwent ultra-deep-next generation sequencing (NGS) in 309 newly diagnosed CLL. A robust bioinformatic algorithm was established for the highly sensitive detection of few TP53 mutated cells (down to 3 out of ′1000 wild-type cells). Minor subclones were validated by independent approaches. Ultra-deep-NGS identified small TP53 mutated subclones in 28/309 (9%) untreated CLL that, due to their very low abundance (median allele frequency: 2.1%), were missed by Sanger sequencing. Patients harboring small TP53 mutated subclones showed the same clinical phenotype and poor survival (hazard ratio = 2.01; P = .0250) as those of patients carrying clonal TP53 lesions. By longitudinal analysis, small TP53 mutated subclones identified before treatment became the predominant population at the time of CLL relapse and anticipated the development of chemorefractoriness. This study provides a proof-of-principle that very minor leukemia subclones detected at diagnosis are an important driver of the subsequent disease course.

Original languageEnglish
Pages (from-to)2139-2147
Number of pages9
JournalBlood
Volume123
Issue number14
DOIs
Publication statusPublished - Apr 3 2014

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ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Rossi, D., Khiabanian, H., Spina, V., Ciardullo, C., Bruscaggin, A., Famà, R., Rasi, S., Monti, S., Deambrogi, C., De Paoli, L., Wang, J., Gattei, V., Guarini, A., Foà, R., Rabadan, R., & Gaidano, G. (2014). Clinical impact of small TP53 mutated subclones in chronic lymphocytic leukemia. Blood, 123(14), 2139-2147. https://doi.org/10.1182/blood-2013-11-539726