Disease evolution and outcomes in familial AML with germline CEBPA mutations

• Published in: Blood Vol. 126; no. 10; pp. 1214 - 1223
• Main Authors: Tawana, Kiran, Wang, Jun, Renneville, Aline, Bödör, Csaba, Hills, Robert, Loveday, Chey, Savic, Aleksandar, Van Delft, Frederik W., Treleaven, Jennifer, Georgiades, Panayiotis, Uglow, Elizabeth, Asou, Norio, Uike, Naokuni, Debeljak, Maruša, Jazbec, Janez, Ancliff, Philip, Gale, Rosemary, Thomas, Xavier, Mialou, Valerie, Döhner, Konstanze, Bullinger, Lars, Mueller, Beatrice, Pabst, Thomas, Stelljes, Matthias, Schlegelberger, Brigitte, Wozniak, Eva, Iqbal, Sameena, Okosun, Jessica, Araf, Shamzah, Frank, Anne-Katrine, Lauridsen, Felicia B., Porse, Bo, Nerlov, Claus, Owen, Carolyn, Dokal, Inderjeet, Gribben, John, Smith, Matthew, Preudhomme, Claude, Chelala, Claude, Cavenagh, Jamie, Fitzgibbon, Jude
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03.09.2015
• Subjects: Adolescent; Adult; CCAAT-Enhancer-Binding Proteins - genetics; Child; Child, Preschool; Disease Progression; Female; Genetic Predisposition to Disease; Germ-Line Mutation; High-Throughput Nucleotide Sequencing; Humans; Infant; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - mortality; Leukemia, Myeloid, Acute - pathology; Male; Middle Aged; Neoplasm Recurrence, Local - genetics; Neoplasm Recurrence, Local - mortality; Neoplasm Recurrence, Local - pathology; Pedigree; Young Adult
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2015-05-647172

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. •Germ-line CEBPA mutations are highly penetrant, causing early-onset de novo AML associated with favorable survival outcomes.•Familial CEBPA-mutated AML displays a unique model of disease progression, with recurrence caused by novel, independent leukemic episodes.