Genomic landscape of patients with germline RUNX1 variants and familial platelet disorder with myeloid malignancy

被引:8
作者
Yu, Kai [1 ]
Deuitch, Natalie [1 ]
Merguerian, Matthew [1 ,2 ]
Cunningham, Lea [1 ,3 ]
Davis, Joie [1 ]
Bresciani, Erica [1 ]
Diemer, Jamie [1 ]
Andrews, Elizabeth [3 ]
Young, Alice [4 ]
Donovan, Frank [5 ]
Sood, Raman [1 ]
Craft, Kathleen [1 ]
Chong, Shawn [1 ]
Chandrasekharappa, Settara [5 ]
Mullikin, Jim [4 ]
Liu, Paul P. [1 ,6 ]
机构
[1] NHGRI, Oncogenesis & Dev Sect, NIH, Bethesda, MD USA
[2] Johns Hopkins Univ, Sch Med, Dept Pediat, Balltimore, MD USA
[3] NCI, Immune Deficiency Cellular Therapy Program, Ctr Canc Res, Bethesda, MD USA
[4] NHGRI, Intramural Sequencing Ctr, NIH, Bethesda, MD 20892 USA
[5] NHGRI, Genom Core, Div Intramural Res, NIH, Bethesda, MD 20892 USA
[6] NHGRI, NIH, 50 South Dr,Bldg 50,Room 5154, Bethesda, MD 20892 USA
关键词
CLONAL HEMATOPOIESIS; WIDE ANALYSIS; MUTATIONS; PREDISPOSITION; TRANSFORMATION; TRANSCRIPTION; ASSOCIATION; SIGNATURES; IMPACT; RISK;
D O I
10.1182/bloodadvances.2023011165
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Familial platelet disorder with associated myeloid malignancies (FPDMM) is caused by germline RUNX1 mutations and characterized by thrombocytopenia and increased risk of hematologic malignancies. We recently launched a longitudinal natural history study for patients with FPDMM. Among 27 families with research genomic data by the end of 2021, 26 different germline RUNX1 variants were detected. Besides missense mutations enriched in Runt homology domain and loss -of -function mutations distributed throughout the gene, spliceregion mutations and large deletions were detected in 6 and 7 families, respectively. In 25 of 51 (49%) patients without hematologic malignancy, somatic mutations were detected in at least 1 of the clonal hematopoiesis of indeterminate potential (CHIP) genes or acute myeloid leukemia (AML) driver genes. BCOR was the most frequently mutated gene (in 9 patients), and multiple BCOR mutations were identified in 4 patients. Mutations in 6 other CHIP- or AML -driver genes (TET2, DNMT3A, KRAS, LRP1B, IDH1, and KMT2C) were also found in >= 2 patients without hematologic malignancy. Moreover, 3 unrelated patients (1 with myeloid malignancy) carried somatic mutations in NFE2, which regulates erythroid and megakaryocytic differentiation. Sequential sequencing data from 19 patients demonstrated dynamic changes of somatic mutations over time, and stable clones were more frequently found in older adult patients. In summary, there are diverse types of germline RUNX1 mutations and high frequency of somatic mutations related to clonal hematopoiesis in patients with FPDMM. Monitoring changes in somatic mutations and clinical manifestations prospectively may reveal mechanisms for malignant progression and inform clinical management. This trial was registered at www. clinicaltrials.gov as #NCT03854318.
引用
收藏
页码:497 / 511
页数:15
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[31]   Somatic mutational landscape of hereditary hematopoietic malignancies caused by germline variants in RUNX1, GATA2, and DDX41 [J].
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Lawrence, David M. ;
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Pozsgai, Matthew J. ;
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Morgan, Neil, V ;
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Owen, Carolyn ;
Patel, Keyur P. ;
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Hsu, Amy P. ;
Holland, Steven M. ;
Phillips, Kerry ;
Poplawski, Nicola K. ;
Babic, Milena ;
Wei, Andrew H. ;
Forsyth, Cecily .
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[32]   Somatic Exonic Deletions in RUNX1 Constitutes a Novel Recurrent Genomic Abnormality in Acute Myeloid Leukemia [J].
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Mathot, Lucy ;
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[33]   TP53, ETV6 and RUNX1 germline variants in a case series of patients developing secondary neoplasms after treatment for childhood acute lymphoblastic leukemia [J].
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Klein, Norman ;
Schreek, Sabine ;
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Moericke, Anja ;
Bleckmann, Kirsten ;
Alten, Julia ;
Dagdan, Elif ;
Cario, Gunnar ;
Kratz, Christian P. ;
Schrappe, Martin ;
Stanulla, Martin .
HAEMATOLOGICA, 2019, 104 (09)
[34]   Mechanisms underlying platelet function defect in a pedigree with familial platelet disorder with a predisposition to acute myelogenous leukemia: potential role for candidate RUNX1 targets [J].
Glembotsky, A. C. ;
Bluteau, D. ;
Espasandin, Y. R. ;
Goette, N. P. ;
Marta, R. F. ;
Marin Oyarzun, C. P. ;
Korin, L. ;
Lev, P. R. ;
Laguens, R. P. ;
Molinas, F. C. ;
Raslova, H. ;
Heller, P. G. .
JOURNAL OF THROMBOSIS AND HAEMOSTASIS, 2014, 12 (05) :761-772
[35]   A novel germline RUNX1 mutation with co-occurrence of somatic alterations in a case of myeloid neoplasm with familial thrombocytopenia: first report from India [J].
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Jain, Arihant ;
Jamwal, Manu ;
Jain, Nidhi ;
Sachdeva, Man U. S. ;
Malhotra, Pankaj ;
Varma, Neelam ;
Das, Reena .
LEUKEMIA & LYMPHOMA, 2019, 60 (10) :2568-2571
[36]   B-cell acute lymphoblastic leukemia in patients with germline RUNX1 mutations [J].
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Gerdemann, Ulrike ;
Brown, Anna L. ;
Place, Andrew E. ;
Cantor, Alan B. ;
Kutny, Matthew A. ;
Avagyan, Serine .
BLOOD ADVANCES, 2021, 5 (16) :3199-3202
[37]   Hereditary platelet disorders associated with germ line variants in RUNX1, ETV6, and ANKRD26 [J].
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Scott, Hamish S. ;
Brown, Anna L. .
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[38]   Mediation analysis reveals common mechanisms of RUNX1 point mutations and RUNX1/RUNX1T1 fusions influencing survival of patients with acute myeloid leukemia [J].
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Batcha, Aarif M. N. ;
Bamopoulos, Stefanos A. ;
Rothenberg-Thurley, Maja ;
Amler, Susanne ;
Sauerlands, Maria Cristina ;
Berdel, Wolfgang E. ;
Woermann, Bernhard J. ;
Bohlander, Stefan K. ;
Braess, Jan ;
Hiddemann, Wolfgang ;
Lehmann, Soren ;
Mareschal, Sylvain ;
Spiekermann, Karsten ;
Metzeler, Klaus H. ;
Herold, Tobias ;
Boulesteix, Anne-Laure .
SCIENTIFIC REPORTS, 2018, 8
[39]   Molecular phenotype and bleeding risks of an inherited platelet disorder in a family with a RUNX1 frameshift mutation [J].
Badin, M. S. ;
Iyer, J. K. ;
Chong, M. ;
Graf, L. ;
Rivard, G. E. ;
Waye, J. . S. ;
Paterson, A. D. ;
Pare, G. ;
Hayward, C. P. M. .
HAEMOPHILIA, 2017, 23 (03) :E204-E213
[40]   Preleukemic and second-hit mutational events in an acute myeloid leukemia patient with a novel germline RUNX1 mutation [J].
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Lee, Joanne ;
Ng, Christopher ;
Kosmo, Bustamin ;
Chiu, Lily ;
Seah, Elaine ;
Mok, Michelle Meng Huang ;
Tan, Karen ;
Osato, Motomi ;
Chng, Wee-Joo ;
Yan, Benedict ;
Tan, Lip Kun .
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