title: Disease evolution and outcomes in familial AML with germline CEBPA mutations.
abstract: In-depth molecular investigation of familial leukemia has been limited by the rarity of recognized cases. This study examines the genetic events initiating leukemia and details the clinical progression of disease across multiple families harboring germ-line CEBPA mutations. Clinical data were collected from 10 CEBPA-mutated families, representing 24 members with acute myeloid leukemia (AML). Whole-exome (WES) and deep sequencing were performed to genetically profile tumors and define patterns of clonal evolution. Germline CEBPA mutations clustered within the N-terminal and were highly penetrant, with AML presenting at a median age of 24.5 years (range, 1.75-46 years). In all diagnostic tumors tested (n = 18), double CEBPA mutations (CEBPAdm) were detected, with acquired (somatic) mutations preferentially targeting the C-terminal. Somatic CEBPA mutations were unstable throughout the disease course, with different mutations identified at recurrence. Deep sequencing of diagnostic and relapse paired samples confirmed that relapse-associated CEBPA mutations were absent at diagnosis, suggesting recurrence was triggered by novel, independent clones. Integrated WES and deep sequencing subsequently revealed an entirely new complement of mutations at relapse, verifying the presentation of a de novo leukemic episode. The cumulative incidence of relapse in familial AML was 56% at 10 years (n = 11), and 3 patients experienced ≥3 disease episodes over a period of 17 to 20 years. Durable responses to secondary therapies were observed, with prolonged median survival after relapse (8 years) and long-term overall survival (10-year overall survival, 67%). Our data reveal that familial CEBPA-mutated AML exhibits a unique model of disease progression, associated with favorable long-term outcomes.
authors.affiliation: Centre for Haemato-Oncology, Barts Cancer Institute, London, United Kingdom;
authors.forename: Kiran
authors.initials: K
authors.lastname: Tawana
authors.affiliation: Centre for Molecular Oncology, Barts Cancer Institute, London, United Kingdom;
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Laboratory of Hematology, Biology and Pathology Center, Centre Hospitalier Régional Universitaire of Lille, Lille, France; University of Lille Nord de France, Lille, France; Inserm, UMR387, Team 3, Cancer Research Institute of Lille, Lille, France;
authors.forename: Aline
authors.initials: A
authors.lastname: Renneville
authors.affiliation: 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary;
authors.forename: Csaba
authors.initials: C
authors.lastname: Bödör
authors.affiliation: School of Medicine, Cardiff University, Cardiff, United Kingdom;
authors.forename: Robert
authors.initials: R
authors.lastname: Hills
authors.affiliation: Centre for Haemato-Oncology, Barts Cancer Institute, London, United Kingdom;
authors.forename: Chey
authors.initials: C
authors.lastname: Loveday
authors.affiliation: Clinic of Hematology, Clinical Center of Vojvodina, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia;
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Savic
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom; The Institute of Cancer Research, Department of Haemato-Oncology, Sutton, United Kingdom;
authors.forename: Frederik W
authors.initials: FW
authors.lastname: Van Delft
authors.affiliation: The Institute of Cancer Research, Department of Haemato-Oncology, Sutton, United Kingdom;
authors.forename: Jennifer
authors.initials: J
authors.lastname: Treleaven
authors.affiliation: Centre for Haemato-Oncology, Barts Cancer Institute, London, United Kingdom;
authors.forename: Panayiotis
authors.initials: P
authors.lastname: Georgiades
authors.affiliation: Centre for Haemato-Oncology, Barts Cancer Institute, London, United Kingdom;
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Uglow
authors.affiliation: Department of Hematology, International Medical Center, Saitama Medical University, Hidaka, Japan;
authors.forename: Norio
authors.initials: N
authors.lastname: Asou
authors.affiliation: Department of Hematology, National Kyushu Cancer Center, Fukuoka, Japan;
authors.forename: Naokuni
authors.initials: N
authors.lastname: Uike
authors.affiliation: Unit for Special laboratory Diagnostics, University Children's Hospital University Medical Center, Ljubljana, Slovenia;
authors.forename: Maruša
authors.initials: M
authors.lastname: Debeljak
authors.affiliation: Unit for Hematology and Oncology, University Children's Hospital University Medical Center, Ljubljana, Slovenia;
authors.forename: Janez
authors.initials: J
authors.lastname: Jazbec
authors.affiliation: Department of Haematology, Great Ormond St Hospital, London, United Kingdom;
authors.forename: Philip
authors.initials: P
authors.lastname: Ancliff
authors.affiliation: Department of Haematology, University College London Cancer Institute, London, United Kingdom;
authors.forename: Rosemary
authors.initials: R
authors.lastname: Gale
authors.affiliation: Department of Hematology, Lyon Sud Hospital, Pierre-Bénite, France;
authors.forename: Xavier
authors.initials: X
authors.lastname: Thomas
authors.affiliation: Institute of Pediatric Hematology and Oncology, Lyon Hospital, Lyon, France;
authors.forename: Valerie
authors.initials: V
authors.lastname: Mialou
authors.affiliation: Department of Internal Medicine III, University of Ulm, Ulm, Germany;
authors.forename: Konstanze
authors.initials: K
authors.lastname: Döhner
authors.affiliation: Department of Internal Medicine III, University of Ulm, Ulm, Germany;
authors.forename: Lars
authors.initials: L
authors.lastname: Bullinger
authors.affiliation: Hematology/Oncology, Department for Clinical Research and Pediatrics, University Hospital Berne and University Berne, Berne, Switzerland;
authors.forename: Beatrice
authors.initials: B
authors.lastname: Mueller
authors.affiliation: Hematology/Oncology, Department for Clinical Research and Pediatrics, University Hospital Berne and University Berne, Berne, Switzerland;
authors.forename: Thomas
authors.initials: T
authors.lastname: Pabst
authors.affiliation: Department of Medicine/Hematology and Oncology, University of Muenster, Muenster, Germany;
authors.forename: Matthias
authors.initials: M
authors.lastname: Stelljes
authors.affiliation: Institute of Human Genetics, Hannover Medical School, Hannover, Germany;
authors.forename: Brigitte
authors.initials: B
authors.lastname: Schlegelberger
authors.affiliation: Genome Centre, Barts and the London School of Medicine and Dentristry, London, United Kingdom;
authors.forename: Eva
authors.initials: E
authors.lastname: Wozniak
authors.affiliation: Centre for Haemato-Oncology, Barts Cancer Institute, London, United Kingdom;
authors.forename: Sameena
authors.initials: S
authors.lastname: Iqbal
authors.affiliation: Centre for Haemato-Oncology, Barts Cancer Institute, London, United Kingdom;
authors.forename: Jessica
authors.initials: J
authors.lastname: Okosun
authors.affiliation: Centre for Haemato-Oncology, Barts Cancer Institute, London, United Kingdom;
authors.forename: Shamzah
authors.initials: S
authors.lastname: Araf
authors.affiliation: The Finsen Laboratory, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark;
authors.forename: Anne-Katrine
authors.initials: AK
authors.lastname: Frank
authors.affiliation: The Finsen Laboratory, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark;
authors.forename: Felicia B
authors.initials: FB
authors.lastname: Lauridsen
authors.affiliation: The Finsen Laboratory, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark; Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark; Danish Stem Cell Centre (DanStem) Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark;
authors.forename: Bo
authors.initials: B
authors.lastname: Porse
authors.affiliation: Medical Research Council Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom;
authors.forename: Claus
authors.initials: C
authors.lastname: Nerlov
authors.affiliation: Division of Hematology and Hematological Malignancies, Foothills Medical Centre, Calgary, Canada; and.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Owen
authors.affiliation: Centre for Paediatrics, Blizard Institute, Barts and the London School of Medicine and Dentistry, London, United Kingdom.
authors.forename: Inderjeet
authors.initials: I
authors.lastname: Dokal
authors.affiliation: Centre for Haemato-Oncology, Barts Cancer Institute, London, United Kingdom;
authors.forename: John
authors.initials: J
authors.lastname: Gribben
authors.affiliation: Centre for Haemato-Oncology, Barts Cancer Institute, London, United Kingdom;
authors.forename: Matthew
authors.initials: M
authors.lastname: Smith
authors.affiliation: Laboratory of Hematology, Biology and Pathology Center, Centre Hospitalier Régional Universitaire of Lille, Lille, France; University of Lille Nord de France, Lille, France; Inserm, UMR387, Team 3, Cancer Research Institute of Lille, Lille, France;
authors.forename: Claude
authors.initials: C
authors.lastname: Preudhomme
authors.affiliation: Centre for Molecular Oncology, Barts Cancer Institute, London, United Kingdom;
authors.forename: Claude
authors.initials: C
authors.lastname: Chelala
authors.affiliation: Centre for Haemato-Oncology, Barts Cancer Institute, London, United Kingdom;
authors.forename: Jamie
authors.initials: J
authors.lastname: Cavenagh
authors.affiliation: Centre for Haemato-Oncology, Barts Cancer Institute, London, United Kingdom;
authors.forename: Jude
authors.initials: J
authors.lastname: Fitzgibbon
mesh_terms: D000293:Adolescent; D000328:Adult; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D018450:Disease Progression; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007223:Infant; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D010375:Pedigree; D055815:Young Adult
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; C515848:CEBPA protein, human