Disease evolution and outcomes in familial AML with germline CEBPA mutations

Item Type:	Article
Title:	Disease evolution and outcomes in familial AML with germline CEBPA mutations
Creators Name:	Tawana, K. and Wang, J. and Renneville, A. and Bödör, C. and Hills, R. and Loveday, C. and Savic, A. and Van Delft, F.W. and Treleaven, J. and Georgiades, P. and Uglow, E. and Asou, N. and Uike, N. and Debeljak, M. and Jazbec, J. and Ancliff, P. and Gale, R. and Thomas, X. and Mialou, V. and Döhner, K. and Bullinger, L. and Mueller, B. and Pabst, T. and Stelljes, M. and Schlegelberger, B. and Wozniak, E. and Iqbal, S. and Okosun, J. and Araf, S. and Frank, A.K. and Lauridsen, F.B. and Porse, B. and Nerlov, C. and Owen, C. and Dokal, I. and Gribben, J. and Smith, M. and Preudhomme, C. and Chelala, C. and Cavenagh, J. and Fitzgibbon, J.
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.
Keywords:	Acute Myeloid Leukemia, CCAAT-Enhancer-Binding Proteins, Disease Progression, Genetic Predisposition to Disease, Germ-Line Mutation, High-Throughput Nucleotide Sequencing, Local Neoplasm Recurrence, Pedigree, Young Adult
Source:	Blood
ISSN:	0006-4971
Publisher:	American Society of Hematology
Volume:	126
Number:	10
Page Range:	1214-1223
Date:	3 September 2015
Official Publication:	https://doi.org/10.1182/blood-2015-05-647172
PubMed:	View item in PubMed

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