Cargando…
Variable outcome and methylation status according to CEBPA mutant type in double-mutated acute myeloid leukemia patients and the possible implications for treatment
Although CEBPA double-mutated (CEBPA(DM)) acute myeloid leukemia is considered to be a favorable-risk disease, relapse remains a major cause of treatment failure. Most CEBPA(DM) patients have a classic biallelic mutant combination with an N-terminal mutation leading to production of p30 protein plus...
Autores principales: | , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Ferrata Storti Foundation
2018
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5777194/ https://www.ncbi.nlm.nih.gov/pubmed/29025912 http://dx.doi.org/10.3324/haematol.2017.173096 |
_version_ | 1783294174909431808 |
---|---|
author | El-Sharkawi, Dima Sproul, Duncan Allen, Christopher G. Feber, Andrew Wright, Melissa Hills, Robert K. Linch, David C. Gale, Rosemary E. |
author_facet | El-Sharkawi, Dima Sproul, Duncan Allen, Christopher G. Feber, Andrew Wright, Melissa Hills, Robert K. Linch, David C. Gale, Rosemary E. |
author_sort | El-Sharkawi, Dima |
collection | PubMed |
description | Although CEBPA double-mutated (CEBPA(DM)) acute myeloid leukemia is considered to be a favorable-risk disease, relapse remains a major cause of treatment failure. Most CEBPA(DM) patients have a classic biallelic mutant combination with an N-terminal mutation leading to production of p30 protein plus a C-terminal loss-of-function in-frame indel mutation (CEBPA(Classic-DM)), but approximately one-third of cases have one or more non-classic mutations, with diverse combinations reported, and there is little information on the consequences of such mutants. We evaluated outcome in a cohort of 104 CEBPA(DM) patients, 79 CEBPA(Classic-DM) and 25 with non-classic mutants, and found that the latter may have poorer survival (5-year overall survival 64% vs. 46%; P=0.05), particularly post relapse (41% vs. 0%; P=0.02). However, for this analysis, all non-classic cases were grouped together, irrespective of mutant combination. As CEBPA(DM) cases have been reported to be hypermethylated, we used methylation profiling to assess whether this could segregate the different mutants. We developed a CEBPA(Classic-DM) methylation signature from a preliminary cohort of 10 CEBPA(DM) (including 8 CEBPA(Classic-DM)) and 30 CEBPA wild-type (CEBPA(WT)) samples, and independently validated the signature in 17 CEBPA(Classic-DM) cases. Assessment of the signature in 16 CEBPA(DM) cases with different non-classic mutant combinations showed that only 31% had a methylation profile equivalent to CEBPA(Classic-DM) whereas for 69% the profile was either intermediate between CEBPA(Classic-DM) and CEBPA(WT) or equivalent to CEBPA(WT). These results suggest that CEBPA(DM) cases with non-classic mutants may be functionally different from those with CEBPA(Classic-DM) mutants, and should not automatically be included in the same prognostic group. (AML12 is registered under ISRCTN17833622 and AML15 under ISRCTN17161961). |
format | Online Article Text |
id | pubmed-5777194 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Ferrata Storti Foundation |
record_format | MEDLINE/PubMed |
spelling | pubmed-57771942018-02-02 Variable outcome and methylation status according to CEBPA mutant type in double-mutated acute myeloid leukemia patients and the possible implications for treatment El-Sharkawi, Dima Sproul, Duncan Allen, Christopher G. Feber, Andrew Wright, Melissa Hills, Robert K. Linch, David C. Gale, Rosemary E. Haematologica Article Although CEBPA double-mutated (CEBPA(DM)) acute myeloid leukemia is considered to be a favorable-risk disease, relapse remains a major cause of treatment failure. Most CEBPA(DM) patients have a classic biallelic mutant combination with an N-terminal mutation leading to production of p30 protein plus a C-terminal loss-of-function in-frame indel mutation (CEBPA(Classic-DM)), but approximately one-third of cases have one or more non-classic mutations, with diverse combinations reported, and there is little information on the consequences of such mutants. We evaluated outcome in a cohort of 104 CEBPA(DM) patients, 79 CEBPA(Classic-DM) and 25 with non-classic mutants, and found that the latter may have poorer survival (5-year overall survival 64% vs. 46%; P=0.05), particularly post relapse (41% vs. 0%; P=0.02). However, for this analysis, all non-classic cases were grouped together, irrespective of mutant combination. As CEBPA(DM) cases have been reported to be hypermethylated, we used methylation profiling to assess whether this could segregate the different mutants. We developed a CEBPA(Classic-DM) methylation signature from a preliminary cohort of 10 CEBPA(DM) (including 8 CEBPA(Classic-DM)) and 30 CEBPA wild-type (CEBPA(WT)) samples, and independently validated the signature in 17 CEBPA(Classic-DM) cases. Assessment of the signature in 16 CEBPA(DM) cases with different non-classic mutant combinations showed that only 31% had a methylation profile equivalent to CEBPA(Classic-DM) whereas for 69% the profile was either intermediate between CEBPA(Classic-DM) and CEBPA(WT) or equivalent to CEBPA(WT). These results suggest that CEBPA(DM) cases with non-classic mutants may be functionally different from those with CEBPA(Classic-DM) mutants, and should not automatically be included in the same prognostic group. (AML12 is registered under ISRCTN17833622 and AML15 under ISRCTN17161961). Ferrata Storti Foundation 2018-01 /pmc/articles/PMC5777194/ /pubmed/29025912 http://dx.doi.org/10.3324/haematol.2017.173096 Text en Copyright© 2018 Ferrata Storti Foundation Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or internal use. Sharing published material for non-commercial purposes is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for commercial purposes is not allowed without permission in writing from the publisher. |
spellingShingle | Article El-Sharkawi, Dima Sproul, Duncan Allen, Christopher G. Feber, Andrew Wright, Melissa Hills, Robert K. Linch, David C. Gale, Rosemary E. Variable outcome and methylation status according to CEBPA mutant type in double-mutated acute myeloid leukemia patients and the possible implications for treatment |
title | Variable outcome and methylation status according to CEBPA mutant type in double-mutated acute myeloid leukemia patients and the possible implications for treatment |
title_full | Variable outcome and methylation status according to CEBPA mutant type in double-mutated acute myeloid leukemia patients and the possible implications for treatment |
title_fullStr | Variable outcome and methylation status according to CEBPA mutant type in double-mutated acute myeloid leukemia patients and the possible implications for treatment |
title_full_unstemmed | Variable outcome and methylation status according to CEBPA mutant type in double-mutated acute myeloid leukemia patients and the possible implications for treatment |
title_short | Variable outcome and methylation status according to CEBPA mutant type in double-mutated acute myeloid leukemia patients and the possible implications for treatment |
title_sort | variable outcome and methylation status according to cebpa mutant type in double-mutated acute myeloid leukemia patients and the possible implications for treatment |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5777194/ https://www.ncbi.nlm.nih.gov/pubmed/29025912 http://dx.doi.org/10.3324/haematol.2017.173096 |
work_keys_str_mv | AT elsharkawidima variableoutcomeandmethylationstatusaccordingtocebpamutanttypeindoublemutatedacutemyeloidleukemiapatientsandthepossibleimplicationsfortreatment AT sproulduncan variableoutcomeandmethylationstatusaccordingtocebpamutanttypeindoublemutatedacutemyeloidleukemiapatientsandthepossibleimplicationsfortreatment AT allenchristopherg variableoutcomeandmethylationstatusaccordingtocebpamutanttypeindoublemutatedacutemyeloidleukemiapatientsandthepossibleimplicationsfortreatment AT feberandrew variableoutcomeandmethylationstatusaccordingtocebpamutanttypeindoublemutatedacutemyeloidleukemiapatientsandthepossibleimplicationsfortreatment AT wrightmelissa variableoutcomeandmethylationstatusaccordingtocebpamutanttypeindoublemutatedacutemyeloidleukemiapatientsandthepossibleimplicationsfortreatment AT hillsrobertk variableoutcomeandmethylationstatusaccordingtocebpamutanttypeindoublemutatedacutemyeloidleukemiapatientsandthepossibleimplicationsfortreatment AT linchdavidc variableoutcomeandmethylationstatusaccordingtocebpamutanttypeindoublemutatedacutemyeloidleukemiapatientsandthepossibleimplicationsfortreatment AT galerosemarye variableoutcomeandmethylationstatusaccordingtocebpamutanttypeindoublemutatedacutemyeloidleukemiapatientsandthepossibleimplicationsfortreatment |