title: Prognostic signature and clonality pattern of recurrently mutated genes in inactive chronic lymphocytic leukemia.
abstract: An increasing numbers of patients are being diagnosed with asymptomatic early-stage chronic lymphocytic leukemia (CLL), with no treatment indication at baseline. We applied a high-throughput deep-targeted analysis, especially designed for covering widely TP53 and ATM genes, in 180 patients with inactive disease at diagnosis, to test the independent prognostic value of CLL somatic recurrent mutations. We found that 40/180 patients harbored at least one acquired variant with ATM (n=17, 9.4%), NOTCH1 (n=14, 7.7%), TP53 (n=14, 7.7%) and SF3B1 (n=10, 5.5%) as most prevalent mutated genes. Harboring one 'sub-Sanger' TP53 mutation granted an independent 3.5-fold increase of probability of needing treatment. Those patients with a double-hit ATM lesion (mutation+11q deletion) had the shorter median time to first treatment (17 months). We found that a genomic variable: TP53 mutations, most of them under the sensitivity of conventional techniques; a cell phenotypic factor: CD38-positive expression; and a classical marker as β2-microglobulin, remained as the unique independent predictors of outcome. The high-throughput determination of TP53 status, particularly in this set of patients frequently lacking high-risk chromosomal aberrations, emerges as a key step, not only for prediction modeling, but also for exploring mutation-specific therapeutic approaches and minimal residual disease monitoring.
authors: Hematology and Medical Oncology Department, Hospital Morales Meseguer, IMIB, Murcia, Spain.
authors: A M
authors: AM
authors: Hurtado
authors: Hematology and Medical Oncology Department, Hospital Morales Meseguer, IMIB, Murcia, Spain.
authors: T-H
authors: TH
authors: Chen-Liang
authors: Traslational Hematology and Oncology Research, Cleveland Clinic, Cleveland, OH, USA.
authors: B
authors: B
authors: Przychodzen
authors: Hematology and Medical Oncology Department, Hospital Morales Meseguer, IMIB, Murcia, Spain.
authors: C
authors: C
authors: Hamedi
authors: Hematology and Medical Oncology Department, Hospital Morales Meseguer, IMIB, Murcia, Spain.
authors: J
authors: J
authors: Muñoz-Ballester
authors: Traslational Hematology and Oncology Research, Cleveland Clinic, Cleveland, OH, USA.
authors: B
authors: B
authors: Dienes
authors: Hematology and Medical Oncology Department, Hospital Morales Meseguer, IMIB, Murcia, Spain.
authors: M D
authors: MD
authors: García-Malo
authors: Hematology and Medical Oncology Department, Hospital Morales Meseguer, IMIB, Murcia, Spain.
authors: A I
authors: AI
authors: Antón
authors: Hematology and Medical Oncology Department, Hospital Morales Meseguer, IMIB, Murcia, Spain.
authors: F
authors: F
authors: de Arriba
authors: Hematology and Medical Oncology Department, Hospital Morales Meseguer, IMIB, Murcia, Spain.
authors: R
authors: R
authors: Teruel-Montoya
authors: Hematology and Medical Oncology Department, Hospital Morales Meseguer, IMIB, Murcia, Spain.
authors: F J
authors: FJ
authors: Ortuño
authors: Hematology and Medical Oncology Department, Hospital Morales Meseguer, IMIB, Murcia, Spain.
authors: V
authors: V
authors: Vicente
authors: Traslational Hematology and Oncology Research, Cleveland Clinic, Cleveland, OH, USA.
authors: J P
authors: JP
authors: Maciejewski
authors: Hematology and Medical Oncology Department, Hospital Morales Meseguer, IMIB, Murcia, Spain.
authors: A
authors: A
authors: Jerez
mesh_terms: D000368:Aged; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency; D052138:Genes, Neoplasm; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D053208:Kaplan-Meier Estimate; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D008297:Male; D009154:Mutation; D011379:Prognosis; D016016:Proportional Hazards Models