Familial AML With Germline CEBPA Mutations: Extended Clinical Outcomes and Analysis Of Secondary Mutations Using Whole Exome Sequencing

• Published in: Blood 2013-11, Vol.122 (21), p.740-740
• Main Authors: Tawana, Kiran, Renneville, Aline, Wang, Jun, Georgiades, Panayiotis, Thomas, Xavier, Mialou, Valerie, Savic, Aleksander, Van Delft, Frederik W, Treleaven, Jennifer G., Iqbal, Sameena, Asou, Norio, Uike, Naokuni, Döhner, Konstanze, Bullinger, Lars, Stelljes, Matthias, Bödör, Csaba, Cavenagh, James D., Steinemann, Doris, Ripperger, Tim, Schlegelberger, Brigitte, Vandenberghe, Peter, Uyttebroeck, Anne, Nomdedeu, Josep F., Hjorth-Hansen, Henrik, Gale, Rosemary E, Toze, Cynthia L., Barnett, Michael J., Zombori, Marianna, Kallay, Krisztian, Pavlu, Jiri, Mutsaers, Pim, Menko, Fred H, Thomas, Angela, Wright, Christine, Okosun, Jessica, Loveday, Chey, Fenaux, Pierre, Scott, Hamish, Preudhomme, Claude, Chelala, Claude, Male, Alison, Owen, Carolyn J., Smith, Matthew, Fitzgibbon, Jude
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V122.21.740.740

Germline mutations in the N-terminal of CCAAT/enhancer binding protein α (CEBPA) are a feature of autosomal dominant AML. Despite the strong penetrance of these mutations, the age of disease onset varies considerably and is usually precipitated by acquiring a C-terminal mutation. Although biallelic CEBPA-mutations in sporadic AML are associated with favorable clinical outcomes, little is known about long-term survival or the secondary molecular events linked with familial cases. We sought to establish the long term clinical outcomes in familial CEBPA-mutated AML and to examine the patterns of secondary mutations associated with leukemic transformation. Disease specific and follow up information was collected in 16 affected patients, from 7 pedigrees, published between 2004 and 2011. In 94% of patients (n=15), at least 3 years follow up was achieved. All pedigrees had a germline N-terminal CEBPA mutation and 17 of 18 documented disease episodes had an acquired C-terminal mutation. The age at AML diagnosis varied from 2-39 years (median 24.5 yrs) with a single asymptomatic carrier detected (now 23 yrs). With the exception of 1 patient diagnosed in 1963, all cases received combination chemotherapy at diagnosis. Additional consolidation comprised autologous stem cell transplantation (SCT, n=3) and allogeneic SCT in 1 patient failing to achieve CR post induction therapy. Ten patients had at least 1 further disease episode, the first recurrence presenting after a median of 2.1 years (range 0.5-14 yrs), 5 continued in CR and 1 patient was lost to follow up. In 3 out of 4 patients, where CEBPA was screened at recurrence, the acquired C-terminal mutations differed from diagnosis, signifying new episodes of AML. The median overall survival (OS) for the entire cohort was 20 years (1.1-46 yrs, n=16) and 17.3 years for patients with multiple disease episodes, reflecting durable responses to second line therapies. To identify potential co-operating mutations in CEBPA pedigrees, whole exome sequencing (WES) was performed in 7 tumor samples from 5 patients across 3 pedigrees, all with the germline mutation p.P23fs (Figure 1). All tumor DNA samples were sequenced with matched remission or skin DNA as a germline control. The number of acquired mutations in familial tumors was similar to sporadic disease, with 10-22 (median=14) non-synonymous tier 1 mutations per sample. In addition to the acquired C-terminal CEBPA mutation, these included established AML loci such as EZH2,