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Mutational Landscape of Patients Referred for Elevated Hemoglobin Level

Background: Since the identification of JAK2 V617F and exon 12 mutations as driver mutations in polycythemia vera (PV) in 2005, molecular testing of these mutations for patients with erythrocytosis has become a routine clinical practice. However, the incidence of myeloid mutations other than the com...

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Autores principales: Bhai, Pratibha, Chin-Yee, Benjamin, Pope, Victor, Cheong, Ian, Matyashin, Maxim, Levy, Michael A., Foroutan, Aidin, Stuart, Alan, Hsia, Cyrus C., Lin, Hanxin, Sadikovic, Bekim, Chin-Yee, Ian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9600330/
https://www.ncbi.nlm.nih.gov/pubmed/36290845
http://dx.doi.org/10.3390/curroncol29100568
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author Bhai, Pratibha
Chin-Yee, Benjamin
Pope, Victor
Cheong, Ian
Matyashin, Maxim
Levy, Michael A.
Foroutan, Aidin
Stuart, Alan
Hsia, Cyrus C.
Lin, Hanxin
Sadikovic, Bekim
Chin-Yee, Ian
author_facet Bhai, Pratibha
Chin-Yee, Benjamin
Pope, Victor
Cheong, Ian
Matyashin, Maxim
Levy, Michael A.
Foroutan, Aidin
Stuart, Alan
Hsia, Cyrus C.
Lin, Hanxin
Sadikovic, Bekim
Chin-Yee, Ian
author_sort Bhai, Pratibha
collection PubMed
description Background: Since the identification of JAK2 V617F and exon 12 mutations as driver mutations in polycythemia vera (PV) in 2005, molecular testing of these mutations for patients with erythrocytosis has become a routine clinical practice. However, the incidence of myeloid mutations other than the common JAK2 V617F mutation in unselected patients referred for elevated hemoglobin is not well studied. This study aimed to characterize the mutational landscape in a real-world population of patients referred for erythrocytosis using a targeted next-generation sequencing (NGS)-based assay. Method: A total of 529 patients (hemoglobin levels >160 g/L in females or >165 g/L in males) were assessed between January 2018 and May 2021 for genetic variants using the Oncomine Myeloid Research Assay (ThermoFisher Scientific, Waltham, MA, USA) targeting 40 key genes with diagnostic and prognostic implications in hematological conditions (17 full genes and 23 genes with clinically relevant “hotspot” regions) and a panel of 29 fusion driver genes (>600 fusion partners). Results: JAK2 mutations were detected in 10.9% (58/529) of patients, with 57 patients positive for JAK2 V617F, while one patient had a JAK2 exon 12 mutation. Additional mutations were detected in 34.5% (20/58) of JAK2-positive patients: TET2 (11; 19%), DNMT3A (2;3.4%), ASXL1 (2; 3.4%), SRSF2 (2; 3.4%), BCOR (1; 1.7%), TP53 (1; 1.7%), and ZRSR2 (1; 1.7%). Diagnosis of PV was suspected in 2 JAK2-negative patients based on the 2016 World Health Organization (WHO) diagnostic criteria. Notably, one patient carried mutations in the SRSF2 and TET2 genes, and the other patient carried mutations in the SRSF2, IDH2, and ASXL1 genes. Three JAK2-negative patients with elevated hemoglobin who tested positive for BCR/ABL1 fusion were diagnosed with chronic myeloid leukemia (CML) and excluded from further analysis. The remaining 466 JAK2-negative patients were diagnosed with secondary erythrocytosis and mutations were found in 6% (28/466) of these cases. Conclusion: Mutations other than JAK2 mutations were frequently identified in patients referred for erythrocytosis, with mutations in the TET2, DNMT3A, and ASXL1 genes being detected in 34.5% of JAK2-positive PV patients. The presence of additional mutations, such as ASXL1 mutations, in this population has implications for prognosis. Both the incidence and mutation type identified in patients with secondary erythrocytosis likely reflects incidental, age-associated clonal hematopoiesis of indeterminate potential (CHIP).
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spelling pubmed-96003302022-10-27 Mutational Landscape of Patients Referred for Elevated Hemoglobin Level Bhai, Pratibha Chin-Yee, Benjamin Pope, Victor Cheong, Ian Matyashin, Maxim Levy, Michael A. Foroutan, Aidin Stuart, Alan Hsia, Cyrus C. Lin, Hanxin Sadikovic, Bekim Chin-Yee, Ian Curr Oncol Article Background: Since the identification of JAK2 V617F and exon 12 mutations as driver mutations in polycythemia vera (PV) in 2005, molecular testing of these mutations for patients with erythrocytosis has become a routine clinical practice. However, the incidence of myeloid mutations other than the common JAK2 V617F mutation in unselected patients referred for elevated hemoglobin is not well studied. This study aimed to characterize the mutational landscape in a real-world population of patients referred for erythrocytosis using a targeted next-generation sequencing (NGS)-based assay. Method: A total of 529 patients (hemoglobin levels >160 g/L in females or >165 g/L in males) were assessed between January 2018 and May 2021 for genetic variants using the Oncomine Myeloid Research Assay (ThermoFisher Scientific, Waltham, MA, USA) targeting 40 key genes with diagnostic and prognostic implications in hematological conditions (17 full genes and 23 genes with clinically relevant “hotspot” regions) and a panel of 29 fusion driver genes (>600 fusion partners). Results: JAK2 mutations were detected in 10.9% (58/529) of patients, with 57 patients positive for JAK2 V617F, while one patient had a JAK2 exon 12 mutation. Additional mutations were detected in 34.5% (20/58) of JAK2-positive patients: TET2 (11; 19%), DNMT3A (2;3.4%), ASXL1 (2; 3.4%), SRSF2 (2; 3.4%), BCOR (1; 1.7%), TP53 (1; 1.7%), and ZRSR2 (1; 1.7%). Diagnosis of PV was suspected in 2 JAK2-negative patients based on the 2016 World Health Organization (WHO) diagnostic criteria. Notably, one patient carried mutations in the SRSF2 and TET2 genes, and the other patient carried mutations in the SRSF2, IDH2, and ASXL1 genes. Three JAK2-negative patients with elevated hemoglobin who tested positive for BCR/ABL1 fusion were diagnosed with chronic myeloid leukemia (CML) and excluded from further analysis. The remaining 466 JAK2-negative patients were diagnosed with secondary erythrocytosis and mutations were found in 6% (28/466) of these cases. Conclusion: Mutations other than JAK2 mutations were frequently identified in patients referred for erythrocytosis, with mutations in the TET2, DNMT3A, and ASXL1 genes being detected in 34.5% of JAK2-positive PV patients. The presence of additional mutations, such as ASXL1 mutations, in this population has implications for prognosis. Both the incidence and mutation type identified in patients with secondary erythrocytosis likely reflects incidental, age-associated clonal hematopoiesis of indeterminate potential (CHIP). MDPI 2022-09-30 /pmc/articles/PMC9600330/ /pubmed/36290845 http://dx.doi.org/10.3390/curroncol29100568 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Bhai, Pratibha
Chin-Yee, Benjamin
Pope, Victor
Cheong, Ian
Matyashin, Maxim
Levy, Michael A.
Foroutan, Aidin
Stuart, Alan
Hsia, Cyrus C.
Lin, Hanxin
Sadikovic, Bekim
Chin-Yee, Ian
Mutational Landscape of Patients Referred for Elevated Hemoglobin Level
title Mutational Landscape of Patients Referred for Elevated Hemoglobin Level
title_full Mutational Landscape of Patients Referred for Elevated Hemoglobin Level
title_fullStr Mutational Landscape of Patients Referred for Elevated Hemoglobin Level
title_full_unstemmed Mutational Landscape of Patients Referred for Elevated Hemoglobin Level
title_short Mutational Landscape of Patients Referred for Elevated Hemoglobin Level
title_sort mutational landscape of patients referred for elevated hemoglobin level
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9600330/
https://www.ncbi.nlm.nih.gov/pubmed/36290845
http://dx.doi.org/10.3390/curroncol29100568
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