Gale, RE; Tawana, K; Wang, J; Renneville, A; Bodor, C; Hills, R; Loveday, C; ... Fitzgibbon, J; + view all Gale, RE; Tawana, K; Wang, J; Renneville, A; Bodor, C; Hills, R; Loveday, C; Savic, A; Van Delft, FW; Treleaven, J; Georgiades, P; Uglow, E; Asou, N; Uike, N; Debeljak, M; Jazbec, J; Ancliff, P; Thomas, X; Mialou, V; Dohner, K; Bullinger, L; Mueller, B; Pabst, T; Stelljes, M; Schlegelberger, B; Wozniak, E; Iqbal, S; Okosun, J; Araf, S; Frank, AK; Lauridsen, FB; Porse, B; Nerlov, C; Owen, C; Dokal, I; Gribben, J; Smith, M; Preudhomme, C; Chelala, C; Cavenagh, J; Fitzgibbon, J; - view fewer (2015) Disease evolution and outcomes in familial AML with germline CEBPA mutations. Blood , 126 (10) pp. 1214-1223. 10.1182/blood-2015-05-647172.

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Abstract

To date, in-depth molecular investigation of familial leukemia has been limited by the rarity of recognized cases. This study comprehensively examines the genetic events initiating leukemia and details the clinical progression of disease across multiple families harboring germline CEBPA mutations. Clinical data were collected from 10 CEBPA-mutated families, representing 24 members with 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 24.5yrs (1.75-46yrs). 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 found to be unstable throughout the disease course, with different mutations identified at disease 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 10yrs (n=11) and 3 patients experienced ≥3 disease episodes over a period of 17-20yrs. Durable responses to secondary therapies were observed, with prolonged median survival post relapse (8yrs) and long term overall survival (10yr OS, 67%). Our data reveal that familial CEBPA-mutated AML exhibits a unique model of disease progression, associated with favorable long term outcomes.

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