Characterisation of a compound in-cis GATA2 germline mutation in a pedigree presenting with myelodysplastic syndrome/acute myeloid leukemia with concurrent thrombocytopenia

Hahn, Christopher; Brautigan, Peter J.; Chong, Chan-Eng; Janssan, A.; Venugopal, Parvathy; Lee, Y.; Tims, A. E.; Horwitz, Marshall S.; Klingler‐Hoffmann, Manuela; Scott, Hamish S.

doi:10.1038/leu.2015.40

Cited by 10 publications

(11 citation statements)

References 15 publications

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“…3,73,74 Now called GATA2 deficiency syndrome (OMIM: 137295 covers the majority of symptoms), there are .100 families and 122 individual cases (7 pediatric cases confirmed de novo). 8,9,[75][76][77][78][79][80][81][82][83][84][85][86] GATA2 is critical for normal adult hematopoiesis by regulating maintenance and selfrenewal of HSCs, as well as differentiation to blood progenitors and mature blood cells (myeloid cells, B and natural killer [NK] lymphocytes, megakaryocytes, and mast cells). It plays an important role in endothelial to hematopoietic transition and definitive hematopoiesis during development.…”

Section: Germline Gata2 Mutations In Gata2 Deficiency Syndromementioning

confidence: 99%

Secondary leukemia in patients with germline transcription factor mutations (RUNX1, GATA2, CEBPA)

Brown

Hahn

Scott

2020

Blood

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Abstract Recognition that germline mutations can predispose individuals to blood cancers, often presenting as secondary leukemias, has largely been driven in the last 20 years by studies of families with inherited mutations in the myeloid transcription factors (TFs) RUNX1, GATA2, and CEBPA. As a result, in 2016, classification of myeloid neoplasms with germline predisposition for each of these and other genes was added to the World Health Organization guidelines. The incidence of germline mutation carriers in the general population or in various clinically presenting patient groups remains poorly defined for reasons including that somatic mutations in these genes are common in blood cancers, and our ability to distinguish germline (inherited or de novo) and somatic mutations is often limited by the laboratory analyses. Knowledge of the regulation of these TFs and their mutant alleles, their interaction with other genes and proteins and the environment, and how these alter the clinical presentation of patients and their leukemias is also incomplete. Outstanding questions that remain for patients with these germline mutations or their treating clinicians include: What is the natural course of the disease? What other symptoms may I develop and when? Can you predict them? Can I prevent them? and What is the best treatment? The resolution of many of the remaining clinical and biological questions and effective evidence-based treatment of patients with these inherited mutations will depend on worldwide partnerships among patients, clinicians, diagnosticians, and researchers to aggregate sufficient longitudinal clinical and laboratory data and integrate these data with model systems.

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Section: Germline Gata2 Mutations In Gata2 Deficiency Syndromementioning

confidence: 99%

Secondary leukemia in patients with germline transcription factor mutations (RUNX1, GATA2, CEBPA)

Brown

Hahn

Scott

2020

Blood

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“…94 The clinical manifestation of the disorder defined by heterozygous inactivating germ line mutations in GATA2 has come to be known as "GATA2 deficiency syndrome" ( Table 2). Patients with GATA2 deficiency syndrome sometimes additionally exhibit nonhematological and noninfectious complications, including deafness, lymphedema, pulmonary alveolar proteinosis (PAP), miscarriage, hypothyroidism, thrombosis, occasional intellectual disability, and other findings, [95][96][97][98][99] including erythema nodosum 95 and other autoimmune disorders. 100 Interestingly, although PAP is ordinarily associated with circulating antibodies to granulocyte-macrophage colony-stimulating factor, individuals with GATA2-associated PAP do not develop these autoantibodies.…”

Section: Gata2 In Diseasementioning

confidence: 99%

“…97 Among individuals with GATA2 deficiency syndrome that progresses to MDS/AML, acquired secondary mutations in the gene encoding chromatin-binding protein ASXL1 are common. 84,91,107 In contradistinction to cancer predisposition syndromes caused by mutations in tumor suppressor genes, however, there is little evidence that, among patients with GATA2 deficiency syndrome, the wild-type copy of GATA2 undergoes an acquired "second hit," not even with leukemic progression, 84,98 as assessed via whole exome 107 or whole genome sequencing 108 performed at depths of coverage sufficient to reveal hematopoietic subclones.…”

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confidence: 99%

GATA factor mutations in hematologic disease

Crispino

Horwitz

2017

Blood

167

133

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GATA family proteins play essential roles in development of many cell types, including hematopoietic, cardiac, and endodermal lineages. The first three factors, GATAs 1, 2, and 3, are essential for normal hematopoiesis, and their mutations are responsible for a variety of blood disorders. Acquired and inherited GATA1 mutations contribute to Diamond-Blackfan anemia, acute megakaryoblastic leukemia, transient myeloproliferative disorder, and a group of related congenital dyserythropoietic anemias with thrombocytopenia. Conversely, germ line mutations in GATA2 are associated with GATA2 deficiency syndrome, whereas acquired mutations are seen in myelodysplastic syndrome, acute myeloid leukemia, and in blast crisis transformation of chronic myeloid leukemia. The fact that mutations in these genes are commonly seen in blood disorders underscores their critical roles and highlights the need to develop targeted therapies for transcription factors. This review focuses on hematopoietic disorders that are associated with mutations in two prominent GATA family members, GATA1 and GATA2.

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“…Confirmed in multiple studies [102][103][104][105][106][107][108] PubMed search was performed using a string (exome OR exom* OR NGS OR "whole genome" OR "next-generation" OR "next generation" OR WES) AND (familial OR hereditary OR susceptib* OR risk OR germline OR "germline") AND (sequencing OR analysis) AND (cancer OR malignancy OR tumor* OR tumour*) AND English [lang]. We considered only those studies, which reported identification of novel genes by exome sequencing.…”

Section: Challenges and Possible Solutionsmentioning

confidence: 53%

Identification of novel hereditary cancer genes by whole exome sequencing

et al. 2015

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Whole exome sequencing (WES) provides a powerful tool for medical genetic research. Several dozens of WES studies involving patients with hereditary cancer syndromes have already been reported. WES led to breakthrough in understanding of the genetic basis of some exceptionally rare syndromes; for example, identification of germ-line SMARCA4 mutations in patients with ovarian hypercalcemic small cell carcinomas indeed explains a noticeable share of familial aggregation of this disease. However, studies on common cancer types turned out to be more difficult. In particular, there is almost a dozen of reports describing WES analysis of breast cancer patients, but none of them yet succeeded to reveal a gene responsible for the significant share of missing heritability. Virtually all components of WES studies require substantial improvement, e.g. technical performance of WES, interpretation of WES results, mode of patient selection, etc. Most of contemporary investigations focus on genes with autosomal dominant mechanism of inheritance; however, recessive and oligogenic models of transmission of cancer susceptibility also need to be considered. It is expected that the list of medically relevant tumor-predisposing genes will be rapidly expanding in the next few years.

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Characterisation of a compound in-cis GATA2 germline mutation in a pedigree presenting with myelodysplastic syndrome/acute myeloid leukemia with concurrent thrombocytopenia

Cited by 10 publications

References 15 publications

Secondary leukemia in patients with germline transcription factor mutations (RUNX1, GATA2, CEBPA)

Secondary leukemia in patients with germline transcription factor mutations (RUNX1, GATA2, CEBPA)

GATA factor mutations in hematologic disease

Identification of novel hereditary cancer genes by whole exome sequencing

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