High Frequency of Copy-Neutral Loss of Heterozygosity in Patients with Myelofibrosis

Paula, Milton Rego de; Nonino, Alexandre; Nascimento, Juliana Minuncio; Bonadio, Raphael Severino; Pic‐Taylor, Aline; Oliveira, Silviene Fabiana de; Pereira, Rinaldo Wellerson; Mascarenhas, Cintia do Couto; Mazzeu, Juliana Forte

doi:10.1159/000487627

Cited by 8 publications

(3 citation statements)

References 34 publications

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“…Our series supports the suggestion that a high MPN-associated mutation VAF may be a useful diagnostic adjunct, as the only categories in which the VAF ratio of spliceosome mutation/MPN-associated mutation was uniformly less than one were these cases with overlapping features between CMML and PMF with monocytosis and cases of blast-phase MPN. The very high MPN VAF in our cases with overlapping features indicated loss of heterozygosity of the mutated MPN gene, a common finding in MPNs,17 47 48 and this is in stark contrast to our cases of straightforward CMML that had very low MPN VAFs, suggesting that the MPN mutation was present in a minor subclone.…”

Section: Discussioncontrasting

confidence: 77%

Clinicopathologic characterisation of myeloid neoplasms with concurrent spliceosome mutations and myeloproliferative-neoplasm-associated mutations

2020

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AimsSpliceosome genes (SF3B1, SRSF2, U2AF1 and ZRSR2) are commonly mutated in myeloid neoplasms, particularly in myelodysplastic syndromes (MDS). JAK2, MPL and CALR mutations are associated with myeloproliferative neoplasms (MPN). Although SF3B1 and MPN-associated mutations frequently co-occur in the rare entity MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T), myeloid neoplasms with concurrent spliceosome and MPN-associated mutations encompass many disease entities and are not well characterised.MethodsSpecimens from 2016 to 2019 with concurrent spliceosome and MPN-associated mutations were identified, and the clinicopathologic features were assessed.ResultsThe 36 cases were divided into mutational categories based on their spliceosome mutation. At diagnosis, cases with concurrent U2AF1 and MPN-associated mutations had lower leucocyte counts and platelet counts than did the other groups. Cases with mutant SRSF2 were more likely to have ASXL1 and IDH2 mutations, while U2AF1-mutated neoplasms were more likely to have an abnormal karyotype. The most common SF3B1 K700 and U2AF1 S34 mutational hotspots were underrepresented in our cohort of myeloid neoplasms with concurrent spliceosome and MPN-associated mutations, as SF3B1 and U2AF1 mutations tended to involve other codons. Numerous WHO-defined disease entities were represented in each spliceosome gene category; although MDS/MPN-RS-T were only identified in the group with SF3B1 mutations, they constituted only 1/4 of the neoplasms in the category.ConclusionsMyeloid neoplasms with different mutant splicing factor and concurrent MPN-associated mutations demonstrate somewhat different clinical and pathologic features, but t he association between genotypes and phenotypes in these overlapping neoplasms is not straightforward.

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Section: Discussioncontrasting

confidence: 77%

Clinicopathologic characterisation of myeloid neoplasms with concurrent spliceosome mutations and myeloproliferative-neoplasm-associated mutations

2020

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“…However, the mechanisms of development of MF are not completely understood. The JAK2 , together with CALR and MPL mutations, is a common triggering factor in Philadelphia chromosome-negative MPNs [17]. The so-called "driver" mutations activate the JAK-STAT signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

Janus kinase V617F mutation detection in patients with myelofibrosis

Nikolova

Yordanov

Damyanova

et al. 2019

Balkan Journal of Medical Genetics

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Myelofibrosis (MF) is characterized by a presence of an extra fibrous tissue in the bone marrow and additional hematopoiesis. The somatic mutation in the Janus kinase 2 (JAK2) gene (V617F) occurs gradually and is detected in about 50.0% of myelofibrosis or essential thrombo-cytopenia (ET) patients. Our aim was to determine the genotype status according to the carriers of the V617F mutation in patients with MF at the Hematology Ward of the University Hospital "Ivan Rilski" in Sofia, Bulgaria. DNA samples were isolated from venous blood of patients with various hematological disorders. DNA was amplified by polymerase chain reaction (PCR) and subsequent restriction analysis was performed using a BsaXI restriction enzyme. The genotype status was determined on 2.0% agarose gel. We analyzed 38 patients initially suspected of carrying MF or osteomyelofibrosis (OMF). After trepanobiopsy, 20 out of 38 patients were confirmed as myelofibrotic (52.6%), 5/38 (13.2%) were diagnosed as ET, 1/38 (2.6%) was diagnosed as myeloproliferative neoplasm (MPN), 6/38 (15.8%) had polycythemia vera (PV). In six patients, the presence of disease was rejected. Patients with MF were divided into three groups according to the JAK2 V617F genotype status: homozygous for the mutation (3/20 or 15.0%), heterozygous (9/20 or 45.0%) and homozygous for the wild type allele (8/20 or 40.0%). The triggering factor of MF is still unknown. It was considered that this factor could have a genetic nature. Mutations in three genes were mainly accepted as an actual predisposing events to this disease: point mutations leading to amino acid substitutions in JAK2 (V617F) and in MPL (W515L, W515K), as well as insertion or deletion in CALK We have proven that carriers of the V617F mutation prevailed in the group of patients with MF (altogether 12 patients or 60.0%). Previous studies also showed that JAK2 V617F is present in more than half of MF patients within their blood-forming cells. Therefore, the risk of evolution to MF could be associated with V617F-mutant allele burden in patients with MPN.

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“…Through the integration of SNV/Indel variants and SCNAs, several genes were identified to harbor one mutated allele in conjunction with LOH of the wild type allele. This phenomenon has been welldocumented to occur with TP53 across tumor types, ATM in lymphoid neoplasms, JAK2 in myeloproliferative neoplasms, and TET2 in myeloid neoplasms [30][31][32][33][34][35][36][37] . We found similar results with these genes (TP53 n = 153, ATM n = 53, JAK2 n = 33, and TET2 n = 30) as well as several other genes.…”

Section: Somatic Genomic Landscapementioning

confidence: 93%

Enhanced clinical assessment of hematologic malignancies through routine paired tumor and normal sequencing

Ptashkin,

Ewalt,

Jayakumaran

et al. 2023

Nat Commun

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Genomic profiling of hematologic malignancies has augmented our understanding of variants that contribute to disease pathogenesis and supported development of prognostic models that inform disease management in the clinic. Tumor only sequencing assays are limited in their ability to identify definitive somatic variants, which can lead to ambiguity in clinical reporting and patient management. Here, we describe the MSK-IMPACT Heme cohort, a comprehensive data set of somatic alterations from paired tumor and normal DNA using a hybridization capture-based next generation sequencing platform. We highlight patterns of mutations, copy number alterations, and mutation signatures in a broad set of myeloid and lymphoid neoplasms. We also demonstrate the power of appropriate matching to make definitive somatic calls, including in patients who have undergone allogeneic stem cell transplant. We expect that this resource will further spur research into the pathobiology and clinical utility of clinical sequencing for patients with hematologic neoplasms.

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High Frequency of Copy-Neutral Loss of Heterozygosity in Patients with Myelofibrosis

Cited by 8 publications

References 34 publications

Clinicopathologic characterisation of myeloid neoplasms with concurrent spliceosome mutations and myeloproliferative-neoplasm-associated mutations

Clinicopathologic characterisation of myeloid neoplasms with concurrent spliceosome mutations and myeloproliferative-neoplasm-associated mutations

Janus kinase V617F mutation detection in patients with myelofibrosis

Enhanced clinical assessment of hematologic malignancies through routine paired tumor and normal sequencing

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