title: Clinical impact of small TP53 mutated subclones in chronic lymphocytic leukemia.
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.
authors: Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy;
authors: Davide
authors: D
authors: Rossi
authors: Hossein
authors: H
authors: Khiabanian
authors: Valeria
authors: V
authors: Spina
authors: Carmela
authors: C
authors: Ciardullo
authors: Alessio
authors: A
authors: Bruscaggin
authors: Rosella
authors: R
authors: Famà
authors: Silvia
authors: S
authors: Rasi
authors: Sara
authors: S
authors: Monti
authors: Clara
authors: C
authors: Deambrogi
authors: Lorenzo
authors: L
authors: De Paoli
authors: Jiguang
authors: J
authors: Wang
authors: Valter
authors: V
authors: Gattei
authors: Anna
authors: A
authors: Guarini
authors: Robin
authors: R
authors: Foà
authors: Raul
authors: R
authors: Rabadan
authors: Gianluca
authors: G
authors: Gaidano
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002999:Clone Cells / Q000378:metabolism / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D016019:Survival Analysis; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D016159:Tumor Suppressor Protein p53