Disease evolution and outcomes in familial AML with germline CEBPA mutations
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Disease evolution and outcomes in familial AML with germline CEBPA mutations. / 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.
In: Blood, Vol. 126, No. 10, 03.09.2015, p. 1214-23.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Disease evolution and outcomes in familial AML with germline CEBPA mutations
AU - Tawana, Kiran
AU - Wang, Jun
AU - Renneville, Aline
AU - Bödör, Csaba
AU - Hills, Robert
AU - Loveday, Chey
AU - Savic, Aleksandar
AU - Van Delft, Frederik W
AU - Treleaven, Jennifer
AU - Georgiades, Panayiotis
AU - Uglow, Elizabeth
AU - Asou, Norio
AU - Uike, Naokuni
AU - Debeljak, Maruša
AU - Jazbec, Janez
AU - Ancliff, Philip
AU - Gale, Rosemary
AU - Thomas, Xavier
AU - Mialou, Valerie
AU - Döhner, Konstanze
AU - Bullinger, Lars
AU - Mueller, Beatrice
AU - Pabst, Thomas
AU - Stelljes, Matthias
AU - Schlegelberger, Brigitte
AU - Wozniak, Eva
AU - Iqbal, Sameena
AU - Okosun, Jessica
AU - Araf, Shamzah
AU - Frank, Anne-Katrine
AU - Lauridsen, Felicia B
AU - Porse, Bo
AU - Nerlov, Claus
AU - Owen, Carolyn
AU - Dokal, Inderjeet
AU - Gribben, John
AU - Smith, Matthew
AU - Preudhomme, Claude
AU - Chelala, Claude
AU - Cavenagh, Jamie
AU - Fitzgibbon, Jude
N1 - © 2015 by The American Society of Hematology.
PY - 2015/9/3
Y1 - 2015/9/3
N2 - 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.
AB - 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.
U2 - 10.1182/blood-2015-05-647172
DO - 10.1182/blood-2015-05-647172
M3 - Journal article
C2 - 26162409
VL - 126
SP - 1214
EP - 1223
JO - Blood
JF - Blood
SN - 0006-4971
IS - 10
ER -
ID: 160407329