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Utility of targeted gene sequencing to differentiate myeloid malignancies from other cytopenic conditions

The National Heart, Lung, and Blood Institute–funded National MDS Natural History Study (NCT02775383) is a prospective cohort study enrolling patients with cytopenia with suspected myelodysplastic syndromes (MDS) to evaluate factors associated with disease. Here, we sequenced 53 genes in bone marrow...

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Autores principales: DeZern, Amy E., Goll, Johannes B., Lindsley, R. Coleman, Bejar, Rafael, Wilson, Steffanie H., Hebert, Donnie, Deeg, Joachim, Zhang, Ling, Gore, Steven, Al Baghdadi, Tareq, Maciejewski, Jaroslaw, Liu, Jane, Padron, Eric, Komrojki, Rami, Saber, Wael, Abel, Gregory, Kroft, Steven H., Harrington, Alexandra, Grimes, Tyler, Reed, Harrison, Fulton, Robert S., DiFronzo, Nancy L., Gillis, Nancy, Sekeres, Mikkael A., Walter, Matthew J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society of Hematology 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10368770/
https://www.ncbi.nlm.nih.gov/pubmed/36947201
http://dx.doi.org/10.1182/bloodadvances.2022008578
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author DeZern, Amy E.
Goll, Johannes B.
Lindsley, R. Coleman
Bejar, Rafael
Wilson, Steffanie H.
Hebert, Donnie
Deeg, Joachim
Zhang, Ling
Gore, Steven
Al Baghdadi, Tareq
Maciejewski, Jaroslaw
Liu, Jane
Padron, Eric
Komrojki, Rami
Saber, Wael
Abel, Gregory
Kroft, Steven H.
Harrington, Alexandra
Grimes, Tyler
Reed, Harrison
Fulton, Robert S.
DiFronzo, Nancy L.
Gillis, Nancy
Sekeres, Mikkael A.
Walter, Matthew J.
author_facet DeZern, Amy E.
Goll, Johannes B.
Lindsley, R. Coleman
Bejar, Rafael
Wilson, Steffanie H.
Hebert, Donnie
Deeg, Joachim
Zhang, Ling
Gore, Steven
Al Baghdadi, Tareq
Maciejewski, Jaroslaw
Liu, Jane
Padron, Eric
Komrojki, Rami
Saber, Wael
Abel, Gregory
Kroft, Steven H.
Harrington, Alexandra
Grimes, Tyler
Reed, Harrison
Fulton, Robert S.
DiFronzo, Nancy L.
Gillis, Nancy
Sekeres, Mikkael A.
Walter, Matthew J.
author_sort DeZern, Amy E.
collection PubMed
description The National Heart, Lung, and Blood Institute–funded National MDS Natural History Study (NCT02775383) is a prospective cohort study enrolling patients with cytopenia with suspected myelodysplastic syndromes (MDS) to evaluate factors associated with disease. Here, we sequenced 53 genes in bone marrow samples harvested from 1298 patients diagnosed with myeloid malignancy, including MDS and non-MDS myeloid malignancy or alternative marrow conditions with cytopenia based on concordance between independent histopathologic reviews (local, centralized, and tertiary to adjudicate disagreements when needed). We developed a novel 2-stage diagnostic classifier based on mutational profiles in 18 of 53 sequenced genes that were sufficient to best predict a diagnosis of myeloid malignancy and among those with a predicted myeloid malignancy, predict whether they had MDS. The classifier achieved a positive predictive value (PPV) of 0.84 and negative predictive value (NPV) of 0.8 with an area under the receiver operating characteristic curve (AUROC) of 0.85 when classifying patients as having myeloid vs no myeloid malignancy based on variant allele frequencies (VAFs) in 17 genes and a PPV of 0.71 and NPV of 0.64 with an AUROC of 0.73 when classifying patients as having MDS vs non-MDS malignancy based on VAFs in 10 genes. We next assessed how this approach could complement histopathology to improve diagnostic accuracy. For 99 of 139 (71%) patients (PPV of 0.83 and NPV of 0.65) with local and centralized histopathologic disagreement in myeloid vs no myeloid malignancy, the classifier-predicted diagnosis agreed with the tertiary pathology review (considered the internal gold standard).
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spelling pubmed-103687702023-07-27 Utility of targeted gene sequencing to differentiate myeloid malignancies from other cytopenic conditions DeZern, Amy E. Goll, Johannes B. Lindsley, R. Coleman Bejar, Rafael Wilson, Steffanie H. Hebert, Donnie Deeg, Joachim Zhang, Ling Gore, Steven Al Baghdadi, Tareq Maciejewski, Jaroslaw Liu, Jane Padron, Eric Komrojki, Rami Saber, Wael Abel, Gregory Kroft, Steven H. Harrington, Alexandra Grimes, Tyler Reed, Harrison Fulton, Robert S. DiFronzo, Nancy L. Gillis, Nancy Sekeres, Mikkael A. Walter, Matthew J. Blood Adv Myeloid Neoplasia The National Heart, Lung, and Blood Institute–funded National MDS Natural History Study (NCT02775383) is a prospective cohort study enrolling patients with cytopenia with suspected myelodysplastic syndromes (MDS) to evaluate factors associated with disease. Here, we sequenced 53 genes in bone marrow samples harvested from 1298 patients diagnosed with myeloid malignancy, including MDS and non-MDS myeloid malignancy or alternative marrow conditions with cytopenia based on concordance between independent histopathologic reviews (local, centralized, and tertiary to adjudicate disagreements when needed). We developed a novel 2-stage diagnostic classifier based on mutational profiles in 18 of 53 sequenced genes that were sufficient to best predict a diagnosis of myeloid malignancy and among those with a predicted myeloid malignancy, predict whether they had MDS. The classifier achieved a positive predictive value (PPV) of 0.84 and negative predictive value (NPV) of 0.8 with an area under the receiver operating characteristic curve (AUROC) of 0.85 when classifying patients as having myeloid vs no myeloid malignancy based on variant allele frequencies (VAFs) in 17 genes and a PPV of 0.71 and NPV of 0.64 with an AUROC of 0.73 when classifying patients as having MDS vs non-MDS malignancy based on VAFs in 10 genes. We next assessed how this approach could complement histopathology to improve diagnostic accuracy. For 99 of 139 (71%) patients (PPV of 0.83 and NPV of 0.65) with local and centralized histopathologic disagreement in myeloid vs no myeloid malignancy, the classifier-predicted diagnosis agreed with the tertiary pathology review (considered the internal gold standard). The American Society of Hematology 2023-03-27 /pmc/articles/PMC10368770/ /pubmed/36947201 http://dx.doi.org/10.1182/bloodadvances.2022008578 Text en Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Myeloid Neoplasia
DeZern, Amy E.
Goll, Johannes B.
Lindsley, R. Coleman
Bejar, Rafael
Wilson, Steffanie H.
Hebert, Donnie
Deeg, Joachim
Zhang, Ling
Gore, Steven
Al Baghdadi, Tareq
Maciejewski, Jaroslaw
Liu, Jane
Padron, Eric
Komrojki, Rami
Saber, Wael
Abel, Gregory
Kroft, Steven H.
Harrington, Alexandra
Grimes, Tyler
Reed, Harrison
Fulton, Robert S.
DiFronzo, Nancy L.
Gillis, Nancy
Sekeres, Mikkael A.
Walter, Matthew J.
Utility of targeted gene sequencing to differentiate myeloid malignancies from other cytopenic conditions
title Utility of targeted gene sequencing to differentiate myeloid malignancies from other cytopenic conditions
title_full Utility of targeted gene sequencing to differentiate myeloid malignancies from other cytopenic conditions
title_fullStr Utility of targeted gene sequencing to differentiate myeloid malignancies from other cytopenic conditions
title_full_unstemmed Utility of targeted gene sequencing to differentiate myeloid malignancies from other cytopenic conditions
title_short Utility of targeted gene sequencing to differentiate myeloid malignancies from other cytopenic conditions
title_sort utility of targeted gene sequencing to differentiate myeloid malignancies from other cytopenic conditions
topic Myeloid Neoplasia
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10368770/
https://www.ncbi.nlm.nih.gov/pubmed/36947201
http://dx.doi.org/10.1182/bloodadvances.2022008578
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