NGS Evaluation of a Bernese Cohort of Unexplained Erythrocytosis Patients

Jalowiec, Katarzyna Aleksandra; Vrotniakaite-Bajerciene, Kristina; Capraru, Annina; Wojtovicova, Tatiana; Joncourt, Raphael; Rovó, Alicia; Porret, Naomi

doi:10.3390/genes12121951

Cited by 5 publications

(10 citation statements)

References 26 publications

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“…In the idiopathic group, there were 7/33 (21%) venous and 7/32 (27%) arterial thrombotic events. We have not observed any thromboembolism in three patients with mutations causing congenital polycythaemia identified by our in-house Next Generation Sequencing (NGS) panel for polycythaemia [ 16 ].…”

Section: Resultsmentioning

confidence: 99%

“…Based on our results, a diagnostic algorithm to investigate JAK2 unmutated polycythaemia is proposed in Figure 5 . The list of 13 genes included in the panel, as described elsewhere [ 16 ], can be found in the footnote to Figure 5 . As a result of limited diagnostic potential using high-performance liquid chromatography (HPLC) [ 23 ], as it may not detect high oxygen affinity hemoglobinopathies, our NGS panel includes mutations in α- or β-globin genes (HBB, HBA1, HBA2) and the use of HPLC is not part of our algorithm.…”

Section: Discussionmentioning

confidence: 99%

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JAK2 Unmutated Polycythaemia—Real-World Data of 10 Years from a Tertiary Reference Hospital

Jalowiec

Vrotniakaite-Bajerciene

Jalowiec³

et al. 2022

JCM

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(1) Background: Polycythaemia is defined by an increase in haemoglobin (Hb) concentration, haematocrit (Hct) or red blood cell (RBC) count above the reference range adjusted to age, sex and living altitude. JAK2 unmutated polycythaemia is frequent but under-investigated in original publications. In this retrospective cohort study, we investigated the clinical and laboratory data, underlying causes, management and outcomes of JAK2 unmutated polycythaemia patients. (2) Methods: The hospital database was searched to identify JAK2 unmutated patients fulfilling WHO 2016 Hb/Hct criteria for PV (Hb >16.5 g/dL in men and >16 g/dL in women, or Hct > 49% in men and >48% in women, or RBC mass > 25% above mean normal predicted value) between 2008 and 2019. Clinical and laboratory data were collected and analysed. (3) Results: From 727,731 screened patients, 294 (0.04%) were included, the median follow-up time was 47 months. Epo and P50 showed no clear pattern in differentiating causes of polycythaemia. In 30%, the cause remained idiopathic, despite extensive work-up. Sleep apnoea was the primary cause, also in patients under 30. Around 20% had received treatment at any time, half of whom had ongoing treatment at the end of follow-up. During follow-up, 17.2% developed a thromboembolic event, of which 8.5% were venous and 8.8% arterial. The mortality was around 3%. (4) Conclusions: Testing for Epo and P50 did not significantly facilitate identification of underlying causes. The frequency of sleep apnoea stresses the need to investigate this condition. Idiopathic forms are common. A diagnostic flowchart based on our data is proposed here. NGS testing should be considered in young patients with persisting polycythaemia, irrespective of Epo and P50 levels.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

JAK2 Unmutated Polycythaemia—Real-World Data of 10 Years from a Tertiary Reference Hospital

Jalowiec

Vrotniakaite-Bajerciene

Jalowiec³

et al. 2022

JCM

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“…Articles were included if they reported genetic analysis of patients with erythrocytosis where MPN and secondary causes were ruled out. A total of 741 articles (within a period from July 2017 to July 2022) were found, and 19 [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 ] of these were included in our summary. The results are summarized in Supplementary File II (Summary of mutations associated with MPN negative erythrocytosis reported in literature between July 2017 and July 2022).…”

Section: Methodsmentioning

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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“…One patient was diagnosed with a red cell membrane disorder, and one had a variant previously identified in a case of triple-negative MPN. 25 A study of five IE patients identified a novel HIF2A exon 12 mutation in one patient (20%) with a family history of arterial thromboembolic events but not erythrocytosis. 26 A 21gene erythrocytosis panel identified known or potentially causal variants in 45.6% of IE patients.…”

Section: Agnostic Ch a L L E Nge S I N Ie : A Long A N D W I N Di Ng ...mentioning

confidence: 98%

“…More comprehensive genetic studies conducted in IE patients have identified potential germline mutations in 6%-23% of participants with low suspicion of an inherited cause and as many as 67% of patients with a high suspicion. [23][24][25][26][27][28][29][30][31][32] In a study using a 13-gene panel for inherited erythrocytosis, 18% (6/34) of IE patients were found to have variants of undetermined significance. No patients had a family history of erythrocytosis, but most were under the age of 35.…”

Section: Agnostic Ch a L L E Nge S I N Ie : A Long A N D W I N Di Ng ...mentioning

confidence: 99%

Idiopathic erythrocytosis: A diagnostic and management challenge with emerging areas for exploration

O'Neill,

O'Connell

2024

Br J Haematol

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SummaryDespite published algorithms for approaching the work‐up of erythrocytosis, a significant proportion of patients are left with uncertainty as to its aetiology and prognosis. The term ‘idiopathic erythrocytosis’ (IE) is applied when known primary and secondary aetiologies have been ruled out. However, the assignment of secondary aetiologies is not always straightforward or evidence based, which can lead to misdiagnosis and heterogeneity in cohort studies. Furthermore, new studies have identified germline or somatic mutations that may affect prognosis. Epidemiological and cohort data are inconsistent as to whether IE increases the risk for complications such as arterial and venous thromboembolism, clonal transformation or comorbid conditions. Randomized trials assessing the role of phlebotomy for long‐term management of IE have not been performed, so treatment remains a vexing problem for clinicians. Standardization of terminology and testing strategies, including comprehensive genetic screening in clinical research, are key to refining our understanding of IE.

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NGS Evaluation of a Bernese Cohort of Unexplained Erythrocytosis Patients

Cited by 5 publications

References 26 publications

JAK2 Unmutated Polycythaemia—Real-World Data of 10 Years from a Tertiary Reference Hospital

JAK2 Unmutated Polycythaemia—Real-World Data of 10 Years from a Tertiary Reference Hospital

Mutational Landscape of Patients Referred for Elevated Hemoglobin Level

Idiopathic erythrocytosis: A diagnostic and management challenge with emerging areas for exploration

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