Format

Send to

Choose Destination
Blood. 2015 Sep 3;126(10):1214-23. doi: 10.1182/blood-2015-05-647172. Epub 2015 Jul 10.

Disease evolution and outcomes in familial AML with germline CEBPA mutations.

Author information

1
Centre for Haemato-Oncology, Barts Cancer Institute, London, United Kingdom;
2
Centre for Molecular Oncology, Barts Cancer Institute, London, United Kingdom;
3
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;
4
1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary;
5
School of Medicine, Cardiff University, Cardiff, United Kingdom;
6
Clinic of Hematology, Clinical Center of Vojvodina, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia;
7
Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom; The Institute of Cancer Research, Department of Haemato-Oncology, Sutton, United Kingdom;
8
The Institute of Cancer Research, Department of Haemato-Oncology, Sutton, United Kingdom;
9
Department of Hematology, International Medical Center, Saitama Medical University, Hidaka, Japan;
10
Department of Hematology, National Kyushu Cancer Center, Fukuoka, Japan;
11
Unit for Special laboratory Diagnostics, University Children's Hospital University Medical Center, Ljubljana, Slovenia;
12
Unit for Hematology and Oncology, University Children's Hospital University Medical Center, Ljubljana, Slovenia;
13
Department of Haematology, Great Ormond St Hospital, London, United Kingdom;
14
Department of Haematology, University College London Cancer Institute, London, United Kingdom;
15
Department of Hematology, Lyon Sud Hospital, Pierre-Bénite, France;
16
Institute of Pediatric Hematology and Oncology, Lyon Hospital, Lyon, France;
17
Department of Internal Medicine III, University of Ulm, Ulm, Germany;
18
Hematology/Oncology, Department for Clinical Research and Pediatrics, University Hospital Berne and University Berne, Berne, Switzerland;
19
Department of Medicine/Hematology and Oncology, University of Muenster, Muenster, Germany;
20
Institute of Human Genetics, Hannover Medical School, Hannover, Germany;
21
Genome Centre, Barts and the London School of Medicine and Dentristry, London, United Kingdom;
22
The Finsen Laboratory, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark;
23
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;
24
Medical Research Council Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom;
25
Division of Hematology and Hematological Malignancies, Foothills Medical Centre, Calgary, Canada; and.
26
Centre for Paediatrics, Blizard Institute, Barts and the London School of Medicine and Dentistry, London, United Kingdom.

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.

PMID:
26162409
DOI:
10.1182/blood-2015-05-647172
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Silverchair Information Systems
Loading ...
Support Center