Identification of Somatic Mutations Associated with Clonal Hematopoiesis in Unprovoked Venous Thromboembolism

Á. Fidalgo-Fernández¹, M. Hernández-Sánchez², A. Marín-Quílez², R. Benito², S. Santos-Mínguez², C. Miguel-Gracía², I. Rodríguez-Iglesias², S. González-Briones², M. García-García¹, M. Quijada-Álamo², A. Hortal³, S. Cadenas Menéndez¹, J.R. González Porras¹, J.M. Hernández-Rivas^1,2, J.M. Bastida¹

¹Hospital Universitario de Salamanca, Salamanca, Spain, ²Cáncer Research Center, Salamanca, Salamanca, Spain, ³Complejo Asistencial de Zamora, Zamora, Spain

Abstract Number: PB2278

Meeting: ISTH 2020 Congress

Theme: Venous Thromboembolism and Cardioembolism » VTE Diagnosis

Background: Up to 50% of patients with venous thromboembolism (VTE) have no obvious risk factors, being classified as idiopathic or unprovoked. Recently, somatic mutations in clonal hematopoiesis of indeterminate potential (CHIP) are common, increase in prevalence with age and not only have been associated with a higher risk for hematologic malignancy but also with atherosclerotic cardiovascular disease. There are no data assessing the incidence of CHIP-mutations in VTE.

Aims: Analyze the presence of somatic CHIP-mutations in blood cells from patients with unprovoked VTE by Next-Generation Sequencing (NGS).

Methods: 486-patients with VTE from the Hospital of Salamanca are included in RIETE database. Sixty-six patients < 70 years with criteria for unprovoked VTE were sequenced searching CHIP mutations. Patients with major risk factors and epidemiological factors were excluded.
The mutational status of the most common mutated regions within 12-genes related to CHIP (DNMT3A,TET2,TP53,ASXL1,SF3B1,IDH1,IDH2,PPM1D,JAK2,NRAS,KRAS and GNAS) was analyzed in peripheral blood mononuclear cells (PBMCs) using a Custom Amplicon panel of NGS; the primers were designed by Paragon Genomics as a CleanPlex-Custom NGS panel. The mean of reads was 2721 [224-9302]; 95% of the regions were sequenced >1000reads. Mutations were validated by high-depth amplicon sequencing (NexteraXT).

Results: NGS analysis revealed the presence of 6 somatic mutations (9%) located in genes DNMT3A, JAK2 and TET2 (Table1). This incidence was higher than previously reported in population studies(< 3%). The most frequently mutated gene was DNMT3A (6%, 4/66). Three out of DNMT3A mutations were truncating leading to a DNMT3A loss-of-function. All CHIP mutations were detected in a low percentage of PBMCs (< 10%) except to one detected in 30% of cells.

Conclusions: This study identified somatic mutations related to CHIP in with unprovoked VTE.
Studies with a larger number of patients are necessary to determine their association with VTE and if CHIP mutations emerge as a new risk factor for VTE.

Funding: GRS1848/A/18,GRS2068/A/19

Age (years)	Gene	cDNA Mutation	Protein Change	Allele frequency
56	JAK2	c.G1849T	p.V617F	8.7
59	DNMT3A	c.2678G>A	p.W893X	29.8
56	DNMT3A	c.2638delA	p.M880fs	2.5
62	DNMT3A	c.2245delG	p.D748fs	2.0
63	DNMT3A	c.G890C	p.W297S	3.1
61	TET2	c.2454delT	p.P818fs	1.9

[Table1. Somatic mutations detected by NGS]

To cite this abstract in AMA style:

Fidalgo-Fernández Á, Hernández-Sánchez M, Marín-Quílez A, Benito R, Santos-Mínguez S, Miguel-Gracía C, Rodríguez-Iglesias I, González-Briones S, García-García M, Quijada-Álamo M, Hortal A, Cadenas Menéndez S, González Porras JR, Hernández-Rivas JM, Bastida JM. Identification of Somatic Mutations Associated with Clonal Hematopoiesis in Unprovoked Venous Thromboembolism [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/identification-of-somatic-mutations-associated-with-clonal-hematopoiesis-in-unprovoked-venous-thromboembolism/. Accessed November 29, 2023.

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