JavaScript NENÍ povolen !

Deletion 20q is a recurrent abnormality in myeloid malignancies. In our previous study, we identified fusion of the additional sex combs-like 1 (ASXL1) and teashirt zinc finger homeobox 2 genes in a patient with myelodysplastic syndrome. The objective of this study was to determine the frequency of ASXL1 breakpoints in a cohort of 36 patients with deletion 20q as the sole cytogenetic aberration. A combination of molecular cytogenetic methods was used to confirm ASXL1 gene alterations in 19 of the 36 patients, and the determination of ASXL1 gene changes in patients with deletion 20q revealed clinical and prognostic impacts.

MeSH
chromozomální delece * MeSH
cytogenetické vyšetření MeSH
lidé MeSH
lidské chromozomy, pár 20 genetika MeSH
myelodysplastické syndromy genetika MeSH
represorové proteiny genetika MeSH
Check Tag
lidé MeSH
Publikační typ
časopisecké články MeSH

Abstrakt

Klinický význam rozsahu del(5q) u nemocných s MDS

Transfuze a hematologie dnes. 2018 ; 24 (Supplementum 2) : 20. (Český hematologický a transfuziologický sjezd)

ISSN 1213-5763
Medvik
Zdroj

Transfuze a hematologie dnes. 2018 ; () : 20.

Medvik
Zdroj

Publikační typ
abstrakt z konference MeSH

Článek

Copy number neutral loss of heterozygosity at 17p and homozygous mutations of TP53 are associated with complex chromosomal aberrations in patients newly diagnosed with myelodysplastic syndromes

Leukemia research. 2016 ; 42 (-) : 7-12. [pub] 20160124

Leuk Res
ISSN 1873-5835
Medvik
Zdroj

Complex karyotypes are seen in approximately 20% of patients with myelodysplastic syndromes (MDS) and are associated with a high risk of transformation to acute myeloid leukemia and poor outcomes in patients. Copy number neutral loss of heterozygosity (CN-LOH, i.e., both copies of a chromosomal pair or their parts originate from one parent) might contribute to increased genomic instability in the bone-marrow cells of patients with MDS. The pathological potential of CN-LOH, which arises as a clonal aberration in a proportion of somatic cells, consists of tumor suppressor gene and oncogene homozygous mutations. The aim of our study was to evaluate the frequency of CN-LOH at 17p in bone-marrow cells of newly diagnosed MDS patients with complex chromosomal aberrations and to assess its correlation with mutations in the TP53 gene (17p13.1). CN-LOH was detected in 40 chromosomal regions in 21 (29%) of 72 patients analyzed. The changes in 27 of the 40 regions identified were sporadic. The most common finding was CN-LOH of the short arm of chromosome 17, which was detected in 13 (18%) of 72 patients. A mutational analysis confirmed the homozygous mutation of TP53 in all CN-LOH 17p patients, among which two frameshift mutations are not registered in the International Agency for Research on Cancer TP53 Database. CN-LOH 17p correlated with aggressive disease (median overall survival 4 months) and was strongly associated with a complex karyotype in the cohort studied, which might cause rapid disease progression in high-risk MDS. No other CN-LOH region previously recorded in MDS or AML patients (1p, 4q, 7q, 11q, 13q, 19q, 21q) was detected in our cohort of patients with complex karyotype examined at the diagnosis of MDS. The LOH region appeared to be balanced (i.e., with no DNA copy number change) when examined with conventional and molecular cytogenetic methods. Therefore, a microarray that detects single-nucleotide polymorphisms is an ideal method with which to identify and further characterize CN-LOH. Our data should specify the prognosis and should lead to the identification of potential targets for therapeutic interventions.

Článek

Získaná uniparentální disomie v buňkách kostní dřeně nemocných s myelodysplastickými syndromy a komplexním karyotypem
[Acquired uniparental disomy in bone-marrow cells of patients with myelodysplastic syndrome and complex karyotype]

Transfuze a hematologie dnes. 2015 ; 21 (3) : 126-134.

ISSN 1213-5763
Medvik
Zdroj

U 10–20 % nemocných s myelodysplastickými syndromy (MDS) je nalézán komplexní karyotyp, který je spojen s vysokým rizikem transformace do akutní myeloidní leukemie (AML) a špatnou prognózou. Jedním z jevů, které se mohou podílet na zvýšené genomové nestabilitě buněk kostní dřeně u nemocných s MDS, je získaná uniparentální disomie (aUPD), tj. stav, kdy obě kopie určitého chromozomu nebo jeho části pochází od jednoho rodiče. Patologický potenciál této změny, která vzniká jako klonální aberace v některých somatických buňkách, spočívá v přítomnosti homozygotních mutací tumor supresorových genů a onkogenů. Cílem studie bylo zjistit frekvenci a význam uniparentální disomie (UPD) v souboru 57 nemocných s MDS a komplexním karyotypem za použití array komparativní genomové hybridizace kombinované s detekcí jednonukleotidových polymorfismů (aCGH/SNP). V souboru 57 nemocných bylo nalezeno celkem 40 oblastí UPD u 21 pacientů (36,8 %). U zhruba poloviny nálezů šlo o sporadický výskyt (19/40). U šesti pacientů byly detekovány UPD na chromozomu X lokalizované v oblastech Xp22.11–Xp22.2 (4/6) a Xq13.3–Xq21.1 (2/6) a u dvou pacientů byla pozorována UPD 17q s proměnlivým rozsahem v pruzích 17q22 až 17q24.2. Nejčastějším nálezem byla aUPD krátkých ramen chromozomu 17, která byla detekována celkem u 13/57 pacientů (22,8 %). U všech 13 pacientů mutační analýza potvrdila homozygotní mutaci genu TP53, z toho dvě nalezené posunové (frameshift) mutace nebyly dosud popsány v databázi IARC (International Agency for Research on Cancer TP53 database). Nález byl spojen s velmi špatnou prognózou (medián přežití 4 měsíce). Vzhledem k četnosti výskytu ve studovaném souboru byla aUPD 17p silně asociována s komplexním karyotypem na rozdíl od jiných v literatuře dosud popsaných oblastí aUPD (1p, 4q, 7q, 11q, 13q, 21q), které nebyly v souboru detekovány vůbec. Oblasti UPD se jeví při analýzách metodami klasické a molekulární cytogenetiky jako balancované, tedy bez změny počtu kopií DNA. Čipové technologie s detekcí jednonukleotidových polymorfismů jsou ideální metodou pro identifikaci a bližší charakterizaci oblastí UPD a s nimi souvisejících genů významných pro vznik a progresi onemocnění.

Complex karyotypes are seen in approximately 20% of patients with myelodysplastic syndromes (MDS) and are associated with a high risk of transformation into acute myeloid leukaemia (AML) and poor prognosis. Acquired uniparental disomy (aUPD, i.e. both copies of a chromosome pair or its part originate from one parent) may contribute to increased genomic instability in bone-marrow cells of patients with MDS. The pathological potential of aUPD, which arises as a clonal aberration in a proportion of somatic cells, involves tumour suppressor gene and oncogene homozygous mutations. The aim of this study was to evaluate the frequency and implications of uniparental disomy (UPD) in a cohort of 57 patients with MDS and complex karyotype using array comparative genomic hybridization with detection of single nucleotide polymorphisms (aCGH/SNP). UPD was found to be present in 40 regions in 21 of 57 patients (36.8%). Almost half of these involved non-recurrent changes (19/40). Chromosome X UPD was detected in six patients (Xp22.11–Xp22.2 in four and Xq13.3–Xq21.1 in two, respectively). UPD of 17q with a variable extent from 17q22 to 17q24.2 was observed in two patients. The most common finding was aUPD of the short arm of chromosome 17, which was detected in 13 of 57 patients (22.8%). Mutational analysis confirmed a homozygous mutation of the TP53 gene in all samples with this finding, including two frameshift mutations that are not registered in the IARC (International Agency for Research on Cancer TP53) database. This finding correlated with very poor prognosis (median OS 4 months). aUPD 17p was strongly associated with complex karyotype in the studied cohort. However, other previously published aUPDs in MDS (1p, 4q, 7q, 11q, 13q, 21q) were not found in our study. UPD regions appear to be balanced (i.e. without change of DNA copies) by conventional and molecular cytogenetic methods. Therefore, aCGH/SNP represents an ideal method for the identification and further characterization of UPDs and affected genes significant for disease development and progression.

Klíčová slova
komplexní karyotyp, refrakterní cytopenie s multilineární dysplazií,
MeSH
akutní myeloidní leukemie genetika MeSH
analýza přežití MeSH
chromozomální delece MeSH
dospělí MeSH
geny p53 * genetika MeSH
homozygot MeSH
jednonukleotidový polymorfismus MeSH
karyotyp MeSH
lidé středního věku MeSH
lidé MeSH
lidské chromozomy, pár 17 genetika MeSH
mutace MeSH
mutační analýza DNA MeSH
myelodysplastické syndromy * genetika MeSH
refrakterní anemie s nadbytkem blastů genetika MeSH
retrospektivní studie MeSH
senioři nad 80 let MeSH
senioři MeSH
srovnávací genomová hybridizace statistika a číselné údaje MeSH
uniparentální disomie * genetika MeSH
vyšetřování kostní dřeně MeSH
Check Tag
dospělí MeSH
lidé středního věku MeSH
lidé MeSH
mužské pohlaví MeSH
senioři nad 80 let MeSH
senioři MeSH
ženské pohlaví MeSH
Publikační typ
práce podpořená grantem MeSH

Článek

Genetic and epigenetic characterization of low-grade gliomas reveals frequent methylation of the MLH3 gene

Genes, chromosomes & cancer. 2015 ; 54 (11) : 655-667. [pub] 20150825

Genes Chromosom Cancer
ISSN 1098-2264
Medvik
Zdroj

Diffuse astrocytomas and oligodendrogliomas (WHO grade II) are the most common histological subtypes of low-grade gliomas (LGGs). Several molecular and epigenetic markers have been identified that predict tumor progression. Our aim was in detail to investigate the genetic and epigenetic background of LGGs and to identify new markers that might play a role in tumor behavior. Twenty-three patients with oligodendroglioma or oligoastrocytoma (LGO) and 22 patients with diffuse astrocytoma (LGA) were investigated using several molecular-cytogenetic and molecular methods to assess their copy number variations, mutational status and level of promoter methylation. The most frequent findings were a 1p/19q codeletion in 83% of LGO and copy-neutral loss of heterozygosity (CN-LOH) of 17p in 72% of LGA. Somatic mutations in the isocitrate dehydrogenase 1 or 2 (IDH1/IDH2) genes were detected in 96% of LGO and 91% of LGA. The O-6-methylguanine-DNA-methyltransferase (MGMT) promoter was methylated in 83% of LGO and 59% of LGA. MutL homolog 3 (MLH3) promoter methylation was observed in 61% of LGO and 27% of LGA. Methylation of the MGMT promoter, 1p/19q codeletion, mutated IDH1, and CN-LOH of 17p were the most frequent genetic aberrations in LGGs. The findings were more diverse in LGA than in LGO. To the best of our knowledge, this is the first time description of methylation of the MLH3 gene promoter in LGGs. Further studies are required to determine the role of the methylated MLH3 promoter and the other aberrations detected.