title: Mutations in epigenetic regulators including SETD2 are gained during relapse in paediatric acute lymphoblastic leukaemia.
abstract: Relapsed paediatric acute lymphoblastic leukaemia (ALL) has high rates of treatment failure. Epigenetic regulators have been proposed as modulators of chemoresistance, here, we sequence genes encoding epigenetic regulators in matched diagnosis-remission-relapse ALL samples. We find significant enrichment of mutations in epigenetic regulators at relapse with recurrent somatic mutations in SETD2, CREBBP, MSH6, KDM6A and MLL2, mutations in signalling factors are not enriched. Somatic alterations in SETD2, including frameshift and nonsense mutations, are present at 12% in a large de novo ALL patient cohort. We conclude that the enrichment of mutations in epigenetic regulators at relapse is consistent with a role in mediating therapy resistance.
authors.affiliation: 1] Department of Pediatric Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Department of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Brenton G
authors.initials: BG
authors.lastname: Mar
authors.affiliation: Department of Internal Medicine III, University of Ulm, Ulm 89081, Germany.
authors.forename: Lars B
authors.initials: LB
authors.lastname: Bullinger
authors.affiliation: Department of Pediatric Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: McLean
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Peter V
authors.initials: PV
authors.lastname: Grauman
authors.affiliation: Department of Pathology, Boston Children's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Marian H
authors.initials: MH
authors.lastname: Harris
authors.affiliation: Biostatistics & Computational Biology, Dana Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors.forename: Kristen
authors.initials: K
authors.lastname: Stevenson
authors.affiliation: Biostatistics & Computational Biology, Dana Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors.forename: Donna S
authors.initials: DS
authors.lastname: Neuberg
authors.affiliation: Human Oncology and Pathogenesis Program and Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Amit U
authors.initials: AU
authors.lastname: Sinha
authors.affiliation: 1] Department of Pediatric Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Department of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Sallan
authors.affiliation: 1] Department of Pediatric Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Department of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Lewis B
authors.initials: LB
authors.lastname: Silverman
authors.affiliation: Department of Pediatrics, Columbia University Medical Center, New York, New York 10032, USA.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Kung
authors.affiliation: Oncoematologia Pediatrica, Azienda Policlinico OVE, 95125, Catania, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Lo Nigro
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Ebert
authors.affiliation: Human Oncology and Pathogenesis Program and Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Armstrong
mesh_terms: D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D044127:Epigenesis, Genetic / Q000235:genetics*; D005091:Exons / Q000235:genetics; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics*; D012008:Recurrence; D017422:Sequence Analysis, DNA; D017211:Treatment Failure
chemical_list: D017931:DNA Primers; D011495:Histone-Lysine N-Methyltransferase; C521636:SETD2 protein, human