title: Detailed analysis of therapy-driven clonal evolution of TP53 mutations in chronic lymphocytic leukemia.
abstract: In chronic lymphocytic leukemia (CLL), the worst prognosis is associated with TP53 defects with the affected patients being potentially directed to alternative treatment. Therapy administration was shown to drive the selection of new TP53 mutations in CLL. Using ultra-deep next-generation sequencing (NGS), we performed a detailed analysis of TP53 mutations' clonal evolution. We retrospectively analyzed samples that were assessed as TP53-wild-type (wt) by FASAY from 20 patients with a new TP53 mutation detected in relapse and 40 patients remaining TP53-wt in relapse. Minor TP53-mutated subclones were disclosed in 18/20 patients experiencing later mutation selection, while only one minor-clone mutation was observed in those patients remaining TP53-wt (n=40). We documented that (i) minor TP53 mutations may be present before therapy and may occur in any relapse; (ii) the majority of TP53-mutated minor clones expand to dominant clone under the selective pressure of chemotherapy, while persistence of minor-clone mutations is rare; (iii) multiple minor-clone TP53 mutations are common and may simultaneously expand. In conclusion, patients with minor-clone TP53 mutations carry a high risk of mutation selection by therapy. Deep sequencing can shift TP53 mutation identification to a period before therapy administration, which might be of particular importance for clinical trials.
authors.affiliation: 1] Center of Molecular Medicine, Central European Institute of Technology, Masaryk University, Brno, Czech Republic [2] Department of Internal Medicine - Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic.
authors.forename: J
authors.initials: J
authors.lastname: Malcikova
authors.affiliation: Center of Molecular Medicine, Central European Institute of Technology, Masaryk University, Brno, Czech Republic.
authors.forename: K
authors.initials: K
authors.lastname: Stano-Kozubik
authors.affiliation: 1] Center of Molecular Medicine, Central European Institute of Technology, Masaryk University, Brno, Czech Republic [2] Department of Internal Medicine - Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic.
authors.forename: B
authors.initials: B
authors.lastname: Tichy
authors.affiliation: Center of Molecular Medicine, Central European Institute of Technology, Masaryk University, Brno, Czech Republic.
authors.forename: B
authors.initials: B
authors.lastname: Kantorova
authors.affiliation: 1] Center of Molecular Medicine, Central European Institute of Technology, Masaryk University, Brno, Czech Republic [2] Department of Internal Medicine - Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic.
authors.forename: S
authors.initials: S
authors.lastname: Pavlova
authors.affiliation: 1] Center of Molecular Medicine, Central European Institute of Technology, Masaryk University, Brno, Czech Republic [2] Department of Internal Medicine - Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic.
authors.forename: N
authors.initials: N
authors.lastname: Tom
authors.affiliation: Center of Molecular Medicine, Central European Institute of Technology, Masaryk University, Brno, Czech Republic.
authors.forename: L
authors.initials: L
authors.lastname: Radova
authors.affiliation: Department of Pathology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic.
authors.forename: J
authors.initials: J
authors.lastname: Smardova
authors.affiliation: Center of Molecular Medicine, Central European Institute of Technology, Masaryk University, Brno, Czech Republic.
authors.forename: F
authors.initials: F
authors.lastname: Pardy
authors.affiliation: 1] Center of Molecular Medicine, Central European Institute of Technology, Masaryk University, Brno, Czech Republic [2] Department of Internal Medicine - Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic.
authors.forename: M
authors.initials: M
authors.lastname: Doubek
authors.affiliation: Department of Internal Medicine - Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic.
authors.forename: Y
authors.initials: Y
authors.lastname: Brychtova
authors.affiliation: 1] Center of Molecular Medicine, Central European Institute of Technology, Masaryk University, Brno, Czech Republic [2] Department of Internal Medicine - Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic.
authors.forename: M
authors.initials: M
authors.lastname: Mraz
authors.affiliation: 1] Center of Molecular Medicine, Central European Institute of Technology, Masaryk University, Brno, Czech Republic [2] Department of Internal Medicine - Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic.
authors.forename: K
authors.initials: K
authors.lastname: Plevova
authors.affiliation: Department of Internal Medicine - Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic.
authors.forename: E
authors.initials: E
authors.lastname: Diviskova
authors.affiliation: Department of Internal Medicine - Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic.
authors.forename: A
authors.initials: A
authors.lastname: Oltova
authors.affiliation: 1] Center of Molecular Medicine, Central European Institute of Technology, Masaryk University, Brno, Czech Republic [2] Department of Internal Medicine - Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic.
authors.forename: J
authors.initials: J
authors.lastname: Mayer
authors.affiliation: 1] Center of Molecular Medicine, Central European Institute of Technology, Masaryk University, Brno, Czech Republic [2] Department of Internal Medicine - Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic.
authors.forename: S
authors.initials: S
authors.lastname: Pospisilova
authors.affiliation: 1] Center of Molecular Medicine, Central European Institute of Technology, Masaryk University, Brno, Czech Republic [2] Department of Internal Medicine - Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic.
authors.forename: M
authors.initials: M
authors.lastname: Trbusek
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D060965:Clonal Evolution / Q000187:drug effects / Q000235:genetics*; D002999:Clone Cells; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D012008:Recurrence; D012189:Retrospective Studies; D015398:Signal Transduction; D016019:Survival Analysis; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53