scholarly journals Detection and characterization of homozygosity of mutated CALR by copy neutral loss of heterozygosity in myeloproliferative neoplasms among cases with high CALR mutation loads or with progressive disease

Haematologica ◽  
2018 ◽  
Vol 104 (5) ◽  
pp. e187-e190 ◽  
Author(s):  
Anna Stengel ◽  
Sabine Jeromin ◽  
Torsten Haferlach ◽  
Manja Meggendorfer ◽  
Wolfgang Kern ◽  
...  
Keyword(s):  
Loss Of Heterozygosity ◽  
Progressive Disease ◽  
Myeloproliferative Neoplasms ◽  
Neutral Loss ◽  
Calr Mutation

scholarly journals Loss of heterozygosity 4q24 and TET2 mutations associated with myelodysplastic/myeloproliferative neoplasms

Blood ◽  
2009 ◽  
Vol 113 (25) ◽  
pp. 6403-6410 ◽  
Author(s):  
Anna M. Jankowska ◽  
Hadrian Szpurka ◽  
Ramon V. Tiu ◽  
Hideki Makishima ◽  
Manuel Afable ◽  
...  
Keyword(s):  
Loss Of Heterozygosity ◽  
Chromosomal Abnormalities ◽  
Myeloproliferative Neoplasms ◽  
Neutral Loss ◽  
Regulatory Gene ◽  
Clinical Analysis ◽  
Gene Marker ◽  
Compound Heterozygous ◽  
Single Nucleotide ◽  
Myeloid Malignancies

Abstract Chromosomal abnormalities are frequent in myeloid malignancies, but in most cases of myelodysplasia (MDS) and myeloproliferative neoplasms (MPN), underlying pathogenic molecular lesions are unknown. We identified recurrent areas of somatic copy number–neutral loss of heterozygosity (LOH) and deletions of chromosome 4q24 in a large cohort of patients with myeloid malignancies including MDS and related mixed MDS/MPN syndromes using single nucleotide polymorphism arrays. We then investigated genes in the commonly affected area for mutations. When we sequenced TET2, we found homozygous and hemizygous mutations. Heterozygous and compound heterozygous mutations were found in patients with similar clinical phenotypes without LOH4q24. Clinical analysis showed most TET2 mutations were present in patients with MDS/MPN (58%), including CMML (6/17) or sAML (32%) evolved from MDS/MPN and typical MDS (10%), suggesting they may play a ubiquitous role in malignant evolution. TET2 mutations affected conserved domains and the N terminus. TET2 is widely expressed in hematopoietic cells but its function is unknown, and it lacks homology to other known genes. The frequency of mutations in this candidate myeloid regulatory gene suggests an important role in the pathogenesis of poor prognosis MDS/MPN and sAML and may act as a disease gene marker for these often cytogenetically normal disorders.

scholarly journals Acquired copy-neutral loss of heterozygosity of chromosome 1p as a molecular event associated with marrow fibrosis in MPL-mutated myeloproliferative neoplasms

Blood ◽  
2013 ◽  
Vol 121 (21) ◽  
pp. 4388-4395 ◽  
Author(s):  
Elisa Rumi ◽  
Daniela Pietra ◽  
Paola Guglielmelli ◽  
Roberta Bordoni ◽  
Ilaria Casetti ◽  
...  
Keyword(s):  
Loss Of Heterozygosity ◽  
Mutant Allele ◽  
Myeloproliferative Neoplasms ◽  
Neutral Loss ◽  
Molecular Event ◽  
Allele Burden ◽  
Chromosome 1P ◽  
Key Points ◽  
Exon 10 ◽  
Marrow Fibrosis

Key Points In MPL exon 10–mutated myeloproliferative neoplasms, the MPL-mutant allele burden varies considerably from about 1% to almost 100%. High mutation burdens originate from acquired copy-neutral loss of heterozygosity of chromosome 1p and are associated with marrow fibrosis.

scholarly journals Copy neutral loss of heterozygosity: a novel chromosomal lesion in myeloid malignancies

Blood ◽  
2010 ◽  
Vol 115 (14) ◽  
pp. 2731-2739 ◽  
Author(s):  
Christine O'Keefe ◽  
Michael A. McDevitt ◽  
Jaroslaw P. Maciejewski
Keyword(s):  
Loss Of Heterozygosity ◽  
Neutral Loss ◽  
Hematologic Malignancies ◽  
Great Promise ◽  
Myeloid Malignancies ◽  
Oncogenic Mutations ◽  
Chromosomal Lesion ◽  
Complete Set ◽  
Underlying Mechanisms

Abstract Single nucleotide polymorphism arrays (SNP-A) have recently been widely applied as a powerful karyotyping tool in numerous translational cancer studies. SNP-A complements traditional metaphase cytogenetics with the unique ability to delineate a previously hidden chromosomal defect, copy neutral loss of heterozygosity (CN-LOH). Emerging data demonstrate that selected hematologic malignancies exhibit abundant CN-LOH, often in the setting of a normal metaphase karyotype and no previously identified clonal marker. In this review, we explore emerging biologic and clinical features of CN-LOH relevant to hematologic malignancies. In myeloid malignancies, CN-LOH has been associated with the duplication of oncogenic mutations with concomitant loss of the normal allele. Examples include JAK2, MPL, c-KIT, and FLT3. More recent investigations have focused on evaluation of candidate genes contained in common CN-LOH and deletion regions and have led to the discovery of tumor suppressor genes, including c-CBL and family members, as well as TET2. Investigations into the underlying mechanisms generating CN-LOH have great promise for elucidating general cancer mechanisms. We anticipate that further detailed characterization of CN-LOH lesions will probably facilitate our discovery of a more complete set of pathogenic molecular lesions, disease and prognosis markers, and better understanding of the initiation and progression of hematologic malignancies.

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

2018 ◽  
Vol 154 (2) ◽  
pp. 62-70 ◽  
Author(s):  
Milton Rego de Paula Junior ◽  
Alexandre Nonino ◽  
Juliana Minuncio Nascimento ◽  
Raphael S. Bonadio ◽  
Aline Pic-Taylor ◽  
...  
Keyword(s):  
Loss Of Heterozygosity ◽  
High Frequency ◽  
Myeloproliferative Neoplasms ◽  
Neutral Loss ◽  
Copy Number Variations ◽  
Chromosome Abnormalities ◽  
Driver Mutations ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
Mutational Status

Myelofibrosis is the rarest and most severe type of Philadelphia-negative classical myeloproliferative neoplasms. Although mutually exclusive driver mutations in JAK2, MPL, or CALR that activate JAK-STAT pathway have been related to the pathogenesis of the disease, chromosome abnormalities have also been associated with the phenotype and prognosis of the disease. Here, we report the use of a chromosomal microarray platform consisting of both oligo and SNP probes to improve the detection of chromosome abnormalities in patients with myelofibrosis. Sixteen patients with myelofibrosis were tested, and the results were compared to karyotype analysis. Driver mutations in JAK2, MPL, or CALR were investigated by PCR and MLPA. Conventional cytogenetics revealed chromosome abnormalities in 3 out of 16 cases (18.7%), while chromosomal microarray analysis detected copy-number variations (CNV) or copy-neutral loss of heterozygosity (CN-LOH) alterations in 11 out of 16 (68.7%) patients. These included 43 CN-LOH, 14 deletions, 1 trisomy, and 1 duplication. Ten patients showed multiple chromosomal abnormalities, varying from 2 to 13 CNVs or CN-LOHs. Mutational status for JAK2, CALR, and MPL by MLPA revealed a total of 3/16 (18.7%) patients positive for the JAK2 V617F mutation, 9 with CALR deletion or insertion and 1 positive for MPL mutation. Considering that most of the CNVs identified were smaller than the karyotype resolution and the high frequency of CN-LOHs in our study, we propose that chromosomal microarray platforms that combine oligos and SNP should be used as a first-tier genetic test in patients with myelofibrosis.

scholarly journals Circulating Cytokine Levels as Markers of Inflammation in Philadelphia Negative Myeloproliferative Neoplasms: Diagnostic and Prognostic Interest

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Julie Mondet ◽  
Kais Hussein ◽  
Pascal Mossuz
Keyword(s):  
Current Knowledge ◽  
Myeloproliferative Neoplasms ◽  
Phenotypic Correlation ◽  
Hematopoietic Malignancies ◽  
Markers Of Inflammation ◽  
Functional Symptoms ◽  
Cytokine Levels ◽  
Clinical Interest ◽  
Circulating Levels

Cytokines are well known mediators of numerous physiological and pathological processes. They contribute to the regulation of normal hematopoiesis but increasing data suggest that they also have a clinical impact in some hematopoietic malignancies. In particular, there is evidence that cytokines are implicated in the functional symptoms of Philadelphia negative myeloproliferative neoplasms (Ph− MPNs), suggesting that evaluation of circulating levels of cytokines could be of clinical interest for the characterization of patients at the time of diagnosis and for disease prognosis. In this review, we present the current knowledge on alteration of circulating cytokine profiles in MPNs and their role in myelofibrosis pathogenesis. Phenotypic correlation, prognostic value of cytokines, and impact of JAK inhibitors are also discussed.

scholarly journals Characterization of CD34+ hematopoietic progenitor cells in JAK2 V617F and CALR -mutated myeloproliferative neoplasms

2016 ◽  
Vol 48 ◽  
pp. 11-15 ◽  
Author(s):  
Anna Angona ◽  
Alberto Alvarez-Larrán ◽  
Beatriz Bellosillo ◽  
Raquel Longarón ◽  
Laura Camacho ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Myeloproliferative Neoplasms ◽  
Jak2 V617f ◽  
Hematopoietic Progenitor Cells ◽  
Hematopoietic Progenitor

scholarly journals Exploring the Genotype–Phenotype Correlation in GBA-Parkinson Disease: Clinical Aspects, Biomarkers, and Potential Modifiers

2021 ◽  
Vol 12 ◽  
Author(s):  
Elisa Menozzi ◽  
Anthony H. V. Schapira
Keyword(s):  
Parkinson Disease ◽  
Progressive Disease ◽  
Clinical Aspects ◽  
Compound Heterozygous ◽  
Pathogenic Variants ◽  
Risk Variants ◽  
Increased Risk ◽  
Severe Motor ◽  
Heterozygous Carriers

Variants in the glucocerebrosidase (GBA) gene are the most common genetic risk factor for Parkinson disease (PD). These include pathogenic variants causing Gaucher disease (GD) (divided into “severe,” “mild,” or “complex”—resulting from recombinant alleles—based on the phenotypic effects in GD) and “risk” variants, which are not associated with GD but nevertheless confer increased risk of PD. As a group, GBA-PD patients have more severe motor and nonmotor symptoms, faster disease progression, and reduced survival compared with noncarriers. However, different GBA variants impact variably on clinical phenotype. In the heterozygous state, “complex” and “severe” variants are associated with a more aggressive and rapidly progressive disease. Conversely, “mild” and “risk” variants portend a more benign course. Homozygous or compound heterozygous carriers usually display severe phenotypes, akin to heterozygous “complex” or “severe” variants carriers. This article reviews genotype–phenotype correlations in GBA-PD, focusing on clinical and nonclinical aspects (neuroimaging and biochemical markers), and explores other disease modifiers that deserve consideration in the characterization of these patients.

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