title: Genomic complexity and dynamics of clonal evolution in childhood acute myeloid leukemia studied with whole-exome sequencing.
abstract: Despite significant improvement in treatment of childhood acute myeloid leukemia (AML), 30% of patients experience disease recurrence, which is still the major cause of treatment failure and death in these patients. To investigate molecular mechanisms underlying relapse, we performed whole-exome sequencing of diagnosis-relapse pairs and matched remission samples from 4 pediatric AML patients without recurrent cytogenetic alterations. Candidate driver mutations were selected for targeted deep sequencing at high coverage, suitable to detect small subclones (0.12%). BiCEBPα mutation was found to be stable and highly penetrant, representing a separate biological and clinical entity, unlike WT1 mutations, which were extremely unstable. Among the mutational patterns underlying relapse, we detected the acquisition of proliferative advantage by signaling activation (PTPN11 and FLT3-TKD mutations) and the increased resistance to apoptosis (hyperactivation of TYK2). We also found a previously undescribed feature of AML, consisting of a hypermutator phenotype caused by SETD2 inactivation. The consequent accumulation of new mutations promotes the adaptability of the leukemia, contributing to clonal selection. We report a novel ASXL3 mutation characterizing a very small subclone (<1%) present at diagnosis and undergoing expansion (60%) at relapse. Taken together, these findings provide molecular clues for designing optimal therapeutic strategies, in terms of target selection, adequate schedule design and reliable response-monitoring techniques.
authors.affiliation: Department of Pediatrics "Lalla Seràgnoli", Hematology-Oncology Unit, University of Bologna, Bologna, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Masetti
authors.affiliation: Department of Pediatrics "Lalla Seràgnoli", Hematology-Oncology Unit, University of Bologna, Bologna, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Castelli
authors.affiliation: Interdepartmental Centre of Cancer Research "G. Prodi", University of Bologna, Bologna, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Astolfi
authors.affiliation: Department of Pediatrics "Lalla Seràgnoli", Hematology-Oncology Unit, University of Bologna, Bologna, Italy.
authors.forename: Salvatore Nicola
authors.initials: SN
authors.lastname: Bertuccio
authors.affiliation: Interdepartmental Centre of Cancer Research "G. Prodi", University of Bologna, Bologna, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Indio
authors.affiliation: Department of Pediatrics "Lalla Seràgnoli", Hematology-Oncology Unit, University of Bologna, Bologna, Italy.|Current address: Stem Cell Group, University College London Cancer Institute, University College London, London, United Kingdom.
authors.forename: Marco
authors.initials: M
authors.lastname: Togni
authors.affiliation: Department of Pediatrics "Lalla Seràgnoli", Hematology-Oncology Unit, University of Bologna, Bologna, Italy.
authors.forename: Tamara
authors.initials: T
authors.lastname: Belotti
authors.affiliation: Department of Pediatrics "Lalla Seràgnoli", Hematology-Oncology Unit, University of Bologna, Bologna, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Serravalle
authors.affiliation: Interdepartmental Centre of Cancer Research "G. Prodi", University of Bologna, Bologna, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Tarantino
authors.affiliation: Department of Pediatric Hematology Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Zecca
authors.affiliation: Department of Woman and Child Health, Laboratory of Hematology-Oncology, University of Padova, Padova, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Pigazzi
authors.affiliation: Department of Woman and Child Health, Laboratory of Hematology-Oncology, University of Padova, Padova, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Basso
authors.affiliation: Department of Pediatrics "Lalla Seràgnoli", Hematology-Oncology Unit, University of Bologna, Bologna, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Pession
authors.affiliation: Department of Pediatric Hematology-Oncology, IRCCS Ospedale Bambino Gesù, Rome, Italy.|University of Pavia, Pavia, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Locatelli
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D060965:Clonal Evolution; D004252:DNA Mutational Analysis; D059472:Exome; D005260:Female; D023281:Genomics; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D008297:Male; D009364:Neoplasm Recurrence, Local; D012074:Remission Induction
keywords: FLT3-TKD mutation; SETD2 mutation; acute myeloid leukemia relapse; pediatric acute myeloid leukemia; whole-exome massively parallel sequencing