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Disease evolution and outcomes in familial AML with germline CEBPA mutations

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Harvard

Tawana, K, Wang, J, Renneville, A, Bödör, 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, Gale, R, Thomas, X, Mialou, V, Döhner, K, Bullinger, L, Mueller, B, Pabst, T, Stelljes, M, Schlegelberger, B, Wozniak, E, Iqbal, S, Okosun, J, Araf, S, Frank, A-K, Lauridsen, FB, Porse, B, Nerlov, C, Owen, C, Dokal, I, Gribben, J, Smith, M, Preudhomme, C, Chelala, C, Cavenagh, J & Fitzgibbon, J 2015, 'Disease evolution and outcomes in familial AML with germline CEBPA mutations' Blood, vol. 126, no. 10, pp. 1214-1223. https://doi.org/10.1182/blood-2015-05-647172

APA

Tawana, K., Wang, J., Renneville, A., Bödör, C., Hills, R., Loveday, C., ... Fitzgibbon, J. (2015). Disease evolution and outcomes in familial AML with germline CEBPA mutations. Blood, 126(10), 1214-1223. https://doi.org/10.1182/blood-2015-05-647172

CBE

Tawana K, Wang J, Renneville A, Bödör 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, Gale R, Thomas X, Mialou V, Döhner K, Bullinger L, Mueller B, Pabst T, Stelljes M, Schlegelberger B, Wozniak E, Iqbal S, Okosun J, Araf S, Frank A-K, Lauridsen FB, Porse B, Nerlov C, Owen C, Dokal I, Gribben J, Smith M, Preudhomme C, Chelala C, Cavenagh J, Fitzgibbon J. 2015. Disease evolution and outcomes in familial AML with germline CEBPA mutations. Blood. 126(10):1214-1223. https://doi.org/10.1182/blood-2015-05-647172

MLA

Vancouver

Tawana K, Wang J, Renneville A, Bödör C, Hills R, Loveday C et al. Disease evolution and outcomes in familial AML with germline CEBPA mutations. Blood. 2015 Sep 3;126(10):1214-1223. https://doi.org/10.1182/blood-2015-05-647172

Author

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. / Disease evolution and outcomes in familial AML with germline CEBPA mutations. In: Blood. 2015 ; Vol. 126, No. 10. pp. 1214-1223.

Bibtex

@article{aab374392ba6499e81e5458611923738,
title = "Disease evolution and outcomes in familial AML with germline CEBPA mutations",
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.",
author = "Kiran Tawana and Jun Wang and Aline Renneville and Csaba B{\"o}d{\"o}r and Robert Hills and Chey Loveday and Aleksandar Savic and {Van Delft}, {Frederik W} and Jennifer Treleaven and Panayiotis Georgiades and Elizabeth Uglow and Norio Asou and Naokuni Uike and Maruša Debeljak and Janez Jazbec and Philip Ancliff and Rosemary Gale and Xavier Thomas and Valerie Mialou and Konstanze D{\"o}hner and Lars Bullinger and Beatrice Mueller and Thomas Pabst and Matthias Stelljes and Brigitte Schlegelberger and Eva Wozniak and Sameena Iqbal and Jessica Okosun and Shamzah Araf and Anne-Katrine Frank and Lauridsen, {Felicia B} and Bo Porse and Claus Nerlov and Carolyn Owen and Inderjeet Dokal and John Gribben and Matthew Smith and Claude Preudhomme and Claude Chelala and Jamie Cavenagh and Jude Fitzgibbon",
note = "Copyright {\circledC} 2015 American Society of Hematology.",
year = "2015",
month = "9",
day = "3",
doi = "10.1182/blood-2015-05-647172",
language = "English",
volume = "126",
pages = "1214--1223",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "10",

}

RIS

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 - Copyright © 2015 American Society of Hematology.

PY - 2015/9/3

Y1 - 2015/9/3

N2 - 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.

AB - 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.

U2 - 10.1182/blood-2015-05-647172

DO - 10.1182/blood-2015-05-647172

M3 - Journal article

VL - 126

SP - 1214

EP - 1223

JO - Blood

JF - Blood

SN - 0006-4971

IS - 10

ER -

ID: 45569303