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 Prevalence and prognostic impact of allelic imbalances associated with leukemic transformation of Philadelphia chromosome–negative myeloproliferative neoplasms

Blood ◽  
2010 ◽  
Vol 115 (14) ◽  
pp. 2882-2890 ◽  
Author(s):  
Nils H. Thoennissen ◽  
Utz O. Krug ◽  
Dhong Hyun Tony Lee ◽  
Norihiko Kawamata ◽  
Gabriela B. Iwanski ◽  
...  
Keyword(s):  
Target Genes ◽  
Chromosomal Abnormalities ◽  
Myeloproliferative Neoplasms ◽  
Neutral Loss ◽  
Philadelphia Chromosome ◽  
Snp Array ◽  
Chronic Phase ◽  
Prognostic Impact ◽  
Leukemic Transformation ◽  
Blast Phase

Abstract Philadelphia chromosome–negative myeloproliferative neoplasms (MPNs) including polycythemia vera, essential thrombocythemia, and primary myelofibrosis show an inherent tendency for transformation into leukemia (MPN-blast phase), which is hypothesized to be accompanied by acquisition of additional genomic lesions. We, therefore, examined chromosomal abnormalities by high-resolution single nucleotide polymorphism (SNP) array in 88 MPN patients, as well as 71 cases with MPN-blast phase, and correlated these findings with their clinical parameters. Frequent genomic alterations were found in MPN after leukemic transformation with up to 3-fold more genomic changes per sample compared with samples in chronic phase (P < .001). We identified commonly altered regions involved in disease progression including not only established targets (ETV6, TP53, and RUNX1) but also new candidate genes on 7q, 16q, 19p, and 21q. Moreover, trisomy 8 or amplification of 8q24 (MYC) was almost exclusively detected in JAK2V617F− cases with MPN-blast phase. Remarkably, copy number–neutral loss of heterozygosity (CNN-LOH) on either 7q or 9p including homozygous JAK2V617F was related to decreased survival after leukemic transformation (P = .01 and P = .016, respectively). Our high-density SNP-array analysis of MPN genomes in the chronic compared with leukemic stage identified novel target genes and provided prognostic insights associated with the evolution to leukemia.

scholarly journals TP53 mutations in myeloid malignancies are either homozygous or hemizygous due to copy number-neutral loss of heterozygosity or deletion of 17p

Leukemia ◽  
2009 ◽  
Vol 24 (1) ◽  
pp. 216-219 ◽  
Author(s):  
M Jasek ◽  
L P Gondek ◽  
N Bejanyan ◽  
R Tiu ◽  
J Huh ◽  
...  
Keyword(s):  
Loss Of Heterozygosity ◽  
Copy Number ◽  
Neutral Loss ◽  
Tp53 Mutations ◽  
Myeloid Malignancies

scholarly journals POLQ suppresses interhomolog recombination and loss of heterozygosity at targeted DNA breaks

2020 ◽  
Vol 117 (37) ◽  
pp. 22900-22909 ◽  
Author(s):  
Luther Davis ◽  
Kevin J. Khoo ◽  
Yinbo Zhang ◽  
Nancy Maizels
Keyword(s):  
Loss Of Heterozygosity ◽  
Neutral Loss ◽  
Genetic Diseases ◽  
Human Cells ◽  
Dominant Negative ◽  
Compound Heterozygous ◽  
Dna Breaks ◽  
End Joining ◽  
Strand Breaks ◽  
In Cis

Interhomolog recombination (IHR) occurs spontaneously in somatic human cells at frequencies that are low but sufficient to ameliorate some genetic diseases caused by heterozygous mutations or autosomal dominant mutations. Here we demonstrate that DNA nicks or double-strand breaks (DSBs) targeted by CRISPR-Cas9 to both homologs can stimulate IHR and associated copy-neutral loss of heterozygosity (cnLOH) in human cells. The frequency of IHR is 10-fold lower at nicks than at DSBs, but cnLOH is evident in a greater fraction of recombinants. IHR at DSBs occurs predominantly via reciprocal end joining. At DSBs, depletion of POLQ caused a dramatic increase in IHR and in the fraction of recombinants exhibiting cnLOH, suggesting that POLQ promotes end joining in cis, which limits breaks available for recombination in trans. These results define conditions that may produce cnLOH as a mutagenic signature in cancer and may, conversely, promote therapeutic correction of both compound heterozygous and dominant negative mutations associated with genetic disease.

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 Chromosomal lesions and uniparental disomy detected by SNP arrays in MDS, MDS/MPD, and MDS-derived AML

Blood ◽  
2008 ◽  
Vol 111 (3) ◽  
pp. 1534-1542 ◽  
Author(s):  
Lukasz P. Gondek ◽  
Ramon Tiu ◽  
Christine L. O'Keefe ◽  
Mikkael A. Sekeres ◽  
Karl S. Theil ◽  
...  
Keyword(s):  
Chromosomal Abnormalities ◽  
Neutral Loss ◽  
Uniparental Disomy ◽  
Nucleotide Polymorphisms ◽  
Myeloproliferative Disease ◽  
Single Nucleotide ◽  
Clinical Prognosis ◽  
Snp Arrays ◽  
Secondary Acute Myeloid Leukemia ◽  
Prognostic Implications

Abstract Using metaphase cytogenetics (MC), chromosomal abnormalities are found in only a proportion of patients with myelodysplastic syndrome (MDS). We hypothesized that with new precise methods more cryptic karyotypic lesions can be uncovered that may show important clinical implications. We have applied 250K single nucleotide polymorphisms (SNP) arrays (SNP-A) to study chromosomal lesions in samples from 174 patients (94 MDS, 33 secondary acute myeloid leukemia [sAML], and 47 myelodysplastic/myeloproliferative disease [MDS/MPD]) and 76 controls. Using SNP-A, aberrations were found in around three-fourths of MDS, MDS/MPD, and sAML (vs 59%, 37%, 53% by MC; in 8% of patients MC was unsuccessful). Previously unrecognized lesions were detected in patients with normal MC and in those with known lesions. Moreover, segmental uniparental disomy (UPD) was found in 20% of MDS, 23% of sAML, and 35% of MDS/MPD patients, a lesion resulting in copy-neutral loss of heterozygosity undetectable by MC. The potential clinical significance of abnormalities detected by SNP-A, but not seen on MC, was demonstrated by their impact on overall survival. UPD involving chromosomes frequently affected by deletions may have prognostic implications similar to the deletions visible by MC. SNP-A–based karyotyping shows superior resolution for chromosomal defects, including UPD. This technique further complements MC to improve clinical prognosis and targeted therapies.

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