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ASXL1 and STAG2 are common mutations in GATA2 deficiency patients with bone marrow disease and myelodysplastic syndrome

Patients with GATA2 deficiencyharbor de novo or inherited germline mutations in the GATA2 transcription factor gene, predisposing them to myeloid malignancies. There is considerable variation in disease progression, even among family members with the same mutation in GATA2. We investigated somatic m...

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Autores principales: West, Robert R., Calvo, Katherine R., Embree, Lisa J., Wang, Weixin, Tuschong, Laura M., Bauer, Thomas R., Tillo, Desiree, Lack, Justin, Droll, Stephenie, Hsu, Amy P., Holland, Steven M., Hickstein, Dennis D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Hematology 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8945308/
https://www.ncbi.nlm.nih.gov/pubmed/34529785
http://dx.doi.org/10.1182/bloodadvances.2021005065
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author West, Robert R.
Calvo, Katherine R.
Embree, Lisa J.
Wang, Weixin
Tuschong, Laura M.
Bauer, Thomas R.
Tillo, Desiree
Lack, Justin
Droll, Stephenie
Hsu, Amy P.
Holland, Steven M.
Hickstein, Dennis D.
author_facet West, Robert R.
Calvo, Katherine R.
Embree, Lisa J.
Wang, Weixin
Tuschong, Laura M.
Bauer, Thomas R.
Tillo, Desiree
Lack, Justin
Droll, Stephenie
Hsu, Amy P.
Holland, Steven M.
Hickstein, Dennis D.
author_sort West, Robert R.
collection PubMed
description Patients with GATA2 deficiencyharbor de novo or inherited germline mutations in the GATA2 transcription factor gene, predisposing them to myeloid malignancies. There is considerable variation in disease progression, even among family members with the same mutation in GATA2. We investigated somatic mutations in 106 patients with GATA2 deficiency to identify acquired mutations that are associated with myeloid malignancies. Myelodysplastic syndrome (MDS) was the most common diagnosis (∼44%), followed by GATA2 bone marrow immunodeficiency disorder (G2BMID; ∼37%). Thirteen percent of the cohort had GATA2 mutations but displayed no disease manifestations. There were no correlations between age or sex with disease progression or survival. Cytogenetic analyses showed a high incidence of abnormalities (∼43%), notably trisomy 8 (∼23%) and monosomy 7 (∼12%), but the changes did not correlate with lower survival. Somatic mutations in ASXL1 and STAG2 were detected in ∼25% of patients, although the mutations were rarely concomitant. Mutations in DNMT3A were found in ∼10% of patients. These somatic mutations were found similarly in G2BMID and MDS, suggesting clonal hematopoiesis in early stages of disease, before the onset of MDS. ASXL1 mutations conferred a lower survival probability and were more prevalent in female patients. STAG2 mutations also conferred a lower survival probability, but did not show a statistically significant sex bias. There was a conspicuous absence of many commonly mutated genes associated with myeloid malignancies, including TET2, IDH1/2, and the splicing factor genes. Notably, somatic mutations in chromatin-related genes and cohesin genes characterized disease progression in GATA2 deficiency.
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spelling pubmed-89453082022-03-28 ASXL1 and STAG2 are common mutations in GATA2 deficiency patients with bone marrow disease and myelodysplastic syndrome West, Robert R. Calvo, Katherine R. Embree, Lisa J. Wang, Weixin Tuschong, Laura M. Bauer, Thomas R. Tillo, Desiree Lack, Justin Droll, Stephenie Hsu, Amy P. Holland, Steven M. Hickstein, Dennis D. Blood Adv Myeloid Neoplasia Patients with GATA2 deficiencyharbor de novo or inherited germline mutations in the GATA2 transcription factor gene, predisposing them to myeloid malignancies. There is considerable variation in disease progression, even among family members with the same mutation in GATA2. We investigated somatic mutations in 106 patients with GATA2 deficiency to identify acquired mutations that are associated with myeloid malignancies. Myelodysplastic syndrome (MDS) was the most common diagnosis (∼44%), followed by GATA2 bone marrow immunodeficiency disorder (G2BMID; ∼37%). Thirteen percent of the cohort had GATA2 mutations but displayed no disease manifestations. There were no correlations between age or sex with disease progression or survival. Cytogenetic analyses showed a high incidence of abnormalities (∼43%), notably trisomy 8 (∼23%) and monosomy 7 (∼12%), but the changes did not correlate with lower survival. Somatic mutations in ASXL1 and STAG2 were detected in ∼25% of patients, although the mutations were rarely concomitant. Mutations in DNMT3A were found in ∼10% of patients. These somatic mutations were found similarly in G2BMID and MDS, suggesting clonal hematopoiesis in early stages of disease, before the onset of MDS. ASXL1 mutations conferred a lower survival probability and were more prevalent in female patients. STAG2 mutations also conferred a lower survival probability, but did not show a statistically significant sex bias. There was a conspicuous absence of many commonly mutated genes associated with myeloid malignancies, including TET2, IDH1/2, and the splicing factor genes. Notably, somatic mutations in chromatin-related genes and cohesin genes characterized disease progression in GATA2 deficiency. American Society of Hematology 2022-01-31 /pmc/articles/PMC8945308/ /pubmed/34529785 http://dx.doi.org/10.1182/bloodadvances.2021005065 Text en © 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.
spellingShingle Myeloid Neoplasia
West, Robert R.
Calvo, Katherine R.
Embree, Lisa J.
Wang, Weixin
Tuschong, Laura M.
Bauer, Thomas R.
Tillo, Desiree
Lack, Justin
Droll, Stephenie
Hsu, Amy P.
Holland, Steven M.
Hickstein, Dennis D.
ASXL1 and STAG2 are common mutations in GATA2 deficiency patients with bone marrow disease and myelodysplastic syndrome
title ASXL1 and STAG2 are common mutations in GATA2 deficiency patients with bone marrow disease and myelodysplastic syndrome
title_full ASXL1 and STAG2 are common mutations in GATA2 deficiency patients with bone marrow disease and myelodysplastic syndrome
title_fullStr ASXL1 and STAG2 are common mutations in GATA2 deficiency patients with bone marrow disease and myelodysplastic syndrome
title_full_unstemmed ASXL1 and STAG2 are common mutations in GATA2 deficiency patients with bone marrow disease and myelodysplastic syndrome
title_short ASXL1 and STAG2 are common mutations in GATA2 deficiency patients with bone marrow disease and myelodysplastic syndrome
title_sort asxl1 and stag2 are common mutations in gata2 deficiency patients with bone marrow disease and myelodysplastic syndrome
topic Myeloid Neoplasia
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8945308/
https://www.ncbi.nlm.nih.gov/pubmed/34529785
http://dx.doi.org/10.1182/bloodadvances.2021005065
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