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

被引：11

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

来源：

BLOOD ADVANCES | 2024年 / 8卷 / 02期

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

页码：497 / 511

页数：15