Serum erythropoietin levels in 696 patients investigated for erythrocytosis with <scp><i>JAK2</i></scp> mutation analysis

Chin‐Yee, Benjamin; Cheong, Ian; Matyashin, Maxim; Lazo‐Langner, Alejandro; Chin‐Yee, Ian; Bhayana, Vipin; Bhai, Pratibha; Lin, Hanxin; Sadiković, Bekim; Hsia, Cyrus C.

doi:10.1002/ajh.26471

Cited by 4 publications

(2 citation statements)

References 7 publications

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“…Top associated proteins, including P-selectin, platelet glycoprotein 1b alpha chain, and thrombospondin-1, play crucial roles in cell adhesion and platelet function had greater concentrations among those with JAK2 44,45 similar to knock-in mice with inducible JAK2 V617F13,46 . Additionally, individuals with JAK2 CHIP had reduced erythropoietin concentrations, which is also observed among individuals with JAK2 myeloproliferative neoplasms (Supplemental Figure 1 and Supplemental Table 4) 47 . Given that many JAK2associated proteins were related to blood cells, we conducted sensitivity analyses in ARIC, additionally adjusting for platelet and white blood cell (WBC) count.…”

Section: Diverse Proteomic Associations Across Chip Driver Genesmentioning

confidence: 68%

Human Plasma Proteomic Profile of Clonal Hematopoiesis

Yu,

Vromman,

Nguyen

et al. 2023

Preprint

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Plasma proteomic profiles associated with subclinical somatic mutations in blood cells may offer novel insights in downstream clinical consequences. Here, we explore such patterns in clonal hematopoiesis of indeterminate potential (CHIP), which links to several cancer and non-cancer outcomes, including coronary artery disease. Among 12,911 ancestrally diverse participants (682 with CHIP) from NHLBI TOPMed with blood-based DNA sequencing and 1,148 common proteins measured by SomaScan, we identified 32 unique proteins associated with the most prevalent driver genes (DNMT3A,TET2, andASXL1) after multiple testing corrections. These associations showed substantial heterogeneity by driver genes, sex, and race, were enriched for immune response and inflammation pathways, and were moderately replicated in UK Biobank (N=48,922) that used Olink for proteomics measurement. Murine single-cell RNA-sequencing data from aortic arch cells, inclusive of resident hematologic cells, in mice withTet2-/-bone marrow and wild-type mice revealed corroborating differential expression ofTET2-associated protein-encoding genes. Lastly, we apply these observations to identify 68 plasma proteins shared between CHIP and coronary artery disease.

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Section: Diverse Proteomic Associations Across Chip Driver Genesmentioning

confidence: 68%

Human Plasma Proteomic Profile of Clonal Hematopoiesis

Yu,

Vromman,

Nguyen

et al. 2023

Preprint

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“…Erythrocytosis is a common reason for referral to hematologists. Distinguishing between PV and secondary causes of erythrocytosis often relies on molecular diagnostics [ 31 ]. Although JAK2 V617F and exon 12 mutations are well described in PV, the genomic landscape is evolving with the description of additional mutations that impact prognosis and risk stratification [ 32 ] and may help guide future management.…”

Section: Discussionmentioning

confidence: 99%

Mutational Landscape of Patients Referred for Elevated Hemoglobin Level

Bhai

Chin‐Yee²,

Pope³

et al. 2022

Current Oncology

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Background: Since the identification of JAK2 V617F and exon 12 mutations as driver mutations in polycythemia vera (PV) in 2005, molecular testing of these mutations for patients with erythrocytosis has become a routine clinical practice. However, the incidence of myeloid mutations other than the common JAK2 V617F mutation in unselected patients referred for elevated hemoglobin is not well studied. This study aimed to characterize the mutational landscape in a real-world population of patients referred for erythrocytosis using a targeted next-generation sequencing (NGS)-based assay. Method: A total of 529 patients (hemoglobin levels >160 g/L in females or >165 g/L in males) were assessed between January 2018 and May 2021 for genetic variants using the Oncomine Myeloid Research Assay (ThermoFisher Scientific, Waltham, MA, USA) targeting 40 key genes with diagnostic and prognostic implications in hematological conditions (17 full genes and 23 genes with clinically relevant “hotspot” regions) and a panel of 29 fusion driver genes (>600 fusion partners). Results: JAK2 mutations were detected in 10.9% (58/529) of patients, with 57 patients positive for JAK2 V617F, while one patient had a JAK2 exon 12 mutation. Additional mutations were detected in 34.5% (20/58) of JAK2-positive patients: TET2 (11; 19%), DNMT3A (2;3.4%), ASXL1 (2; 3.4%), SRSF2 (2; 3.4%), BCOR (1; 1.7%), TP53 (1; 1.7%), and ZRSR2 (1; 1.7%). Diagnosis of PV was suspected in 2 JAK2-negative patients based on the 2016 World Health Organization (WHO) diagnostic criteria. Notably, one patient carried mutations in the SRSF2 and TET2 genes, and the other patient carried mutations in the SRSF2, IDH2, and ASXL1 genes. Three JAK2-negative patients with elevated hemoglobin who tested positive for BCR/ABL1 fusion were diagnosed with chronic myeloid leukemia (CML) and excluded from further analysis. The remaining 466 JAK2-negative patients were diagnosed with secondary erythrocytosis and mutations were found in 6% (28/466) of these cases. Conclusion: Mutations other than JAK2 mutations were frequently identified in patients referred for erythrocytosis, with mutations in the TET2, DNMT3A, and ASXL1 genes being detected in 34.5% of JAK2-positive PV patients. The presence of additional mutations, such as ASXL1 mutations, in this population has implications for prognosis. Both the incidence and mutation type identified in patients with secondary erythrocytosis likely reflects incidental, age-associated clonal hematopoiesis of indeterminate potential (CHIP).

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