During progression of chronic myeloid leukemia (CML) from the chronic to the accelerated phase and/or blast crisis, clonal evolution with nonrandom secondary aberrations such as +8, +Ph, i(17q), +19, -Y, +21, +17, and -7 is frequently observed. Complex chromosomal rearrangements (CCR) are rather rare, and the significance and frequency of different anomalies are poorly understood. The aim of this study was to determine the chromosomes and chromosomal regions which are involved in CCR during progression of the disease and the frequency of nonrandom changes. Conventional cytogenetics, FISH, and multicolor FISH (mFISH) were used to study karyotypes of 18 CML patients with CCR ascertained by G-banding. Most often involved in CCR were chromosomes 2 (x6); 3, 7, and 17 (x5); 1 and 4 (x4); and 5, 6, 11, and 12 (x3); regions 1q, 2q, 5q, 7p, and 17p; and breakpoints 17p11.2 (x3) and 7p15 (x2). There were no recurrent complex translocations. The present findings demonstrate the very high instability of the genome of malignant cells at the chromosomal level. Precise determination of breakpoints involved in CCR can give new dimension to the understanding of genetic mechanisms which play role in progression of malignant disease.

• MeSH
• bcr-abl fúzní proteiny genetika   MeSH
• chromozomální aberace MeSH
• chronická myeloidní leukemie genetika   MeSH
• dospělí MeSH
• filadelfský chromozom MeSH
• financování organizované MeSH
• hybridizace in situ fluorescenční MeSH
• karyotypizace MeSH
• lidé MeSH
• lidské chromozomy, pár 2 genetika   MeSH
• messenger RNA analýza   MeSH
• polymerázová řetězová reakce s reverzní transkripcí MeSH
• pruhování chromozomů MeSH
• translokace genetická MeSH
• zlomy chromozomů MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH

• MeSH
• chromozomální aberace MeSH
• chromozomy účinky léků   MeSH
• mitóza MeSH
• platina analogy a deriváty   terapeutické užití   MeSH
• rostliny MeSH

• MeSH
• chromozomální aberace MeSH
• cytogenetika MeSH
• dítě MeSH
• genetické nemoci vrozené diagnóza   etiologie   MeSH
• lidé MeSH
• prenatální diagnóza MeSH
• rodokmen MeSH
• translokace genetická MeSH
• vrozené vady etiologie   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH

Human malignancies are often hallmarked with genomic instability, which itself is also considered a causative event in malignant transformation. Genomic instability may manifest itself as genetic changes in the nucleotide sequence of DNA, or as structural or numerical changes of chromosomes. Unrepaired or insufficiently repaired DNA double-strand breaks, as well as telomere shortening, are important contributors in the formation of structural chromosomal aberrations (CAs). In the present review, we discuss potential mechanisms behind the formation of CAs and their relation to cancer. Based on our own studies, we also illustrate how inherited genetic variation may modify the frequency and types of CAs occurring in humans. Recently, we published a series of studies on variations in genes relevant to maintaining genomic integrity, such as those encoding xenobiotic-metabolising enzymes, DNA repair, the tumour suppressor TP53, the spindle assembly checkpoint, and cyclin D1 (CCND1). While individually genetic variation in these genes exerted small modulating effects, in interactions they were associated with CA frequencies in peripheral blood lymphocytes of healthy volunteers. Moreover, we observed opposite associations between the CCND1 splice site polymorphism rs9344 G870A and the frequency of CAs compared to their association with translocation t(11,14). We discuss the functional consequences of the CCND1 gene in interplay with DNA damage response and DNA repair during malignant transformation. Our review summarizes existing evidence that gene variations in relevant cellular pathways modulate the frequency of CAs, predominantly in a complex interaction. More functional/mechanistic studies elucidating these observations are required. Several questions emerge, such as the role of CAs in malignancies with respect to a particular phenotype and heterogeneity, the formation of CAs during the process of malignant transformation, and the formation of CAs in individual types of lymphocytes in relation to the immune response.

• MeSH
• chromozomální aberace * MeSH
• lidé MeSH
• nádory genetika   patologie   MeSH
• oprava DNA * MeSH
• polymorfismus genetický * MeSH
• poškození DNA * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

We analyzed complex chromosomal aberrations in 37 adult patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) using classical cytogenetic method, FISH with locus-specific probes, multicolor FISH (mFISH) and multicolor banding (mBAND). Unbalanced structural aberrations, leading to a gain or loss of chromosomal material, were frequently observed in bone marrow cells. In 30 patients (81.1%) loss or rearrangement of chromosome 5, 7 and/or 11 was found. The most frequent numerical change was trisomy 8 as expected (detected in six patients-16.2%) and the most frequent breakpoints 5q13, 5q33, 7q31, 10p12, 11q23, 12p13, 17p11 and 21q22 were determined.

• MeSH
• akutní erytroblastická leukemie genetika   patologie   MeSH
• buňky kostní dřeně fyziologie   patologie   MeSH
• chromozomální aberace MeSH
• dějiny 16. století MeSH
• dospělí MeSH
• financování organizované MeSH
• genová přestavba genetika   MeSH
• hybridizace in situ fluorescenční MeSH
• karyotypizace MeSH
• lidé středního věku MeSH
• lidé MeSH
• lidské chromozomy genetika   MeSH
• myelodysplastické syndromy genetika   patologie   MeSH
• senioři MeSH
• Check Tag
• dějiny 16. století MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• historické články MeSH

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.

• MeSH
• chromozomální aberace * MeSH
• dospělí MeSH
• genová dávka * MeSH
• hybridizace in situ fluorescenční MeSH
• jednonukleotidový polymorfismus MeSH
• lidé středního věku MeSH
• lidé MeSH
• lidské chromozomy, pár 17 genetika   MeSH
• mutace MeSH
• mutační analýza DNA MeSH
• myelodysplastické syndromy genetika   MeSH
• nádorový supresorový protein p53 genetika   MeSH
• retrospektivní studie MeSH
• sekvenční analýza hybridizací s uspořádaným souborem oligonukleotidů MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• variabilita počtu kopií segmentů DNA MeSH
• vysoce účinné nukleotidové sekvenování MeSH
• ztráta heterozygozity genetika   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
• časopisecké články MeSH
• práce podpořená grantem MeSH

Human cancers are often associated with numerical and structural chromosomal instability. Structural chromosomal aberrations (CAs) in peripheral blood lymphocytes (PBL) arise as consequences of direct DNA damage or due to replication on a damaged DNA template. In both cases, DNA repair is critical and inter-individual differences in its capacity are probably due to corresponding genetic variations. We investigated functional variants in DNA repair genes (base and nucleotide excision repair, double-strand break repair) in relation to CAs, chromatid-type aberrations (CTAs) and chromosome-type aberrations (CSAs) in healthy individuals. Chromosomal damage was determined by conventional cytogenetic analysis. The genotyping was performed by both restriction fragment length polymorphism and TaqMan allelic discrimination assays. Multivariate logistic regression was applied for testing individual factors on CAs, CTAs and CSAs. Pair-wise genotype interactions of 11 genes were constructed for all possible pairs of single-nucleotide polymorphisms. Analysed individually, we observed significantly lower CTA frequencies in association with XPD Lys751Gln homozygous variant genotype [odds ratio (OR) 0.64, 95% confidence interval (CI) 0.48-0.85, P = 0.004; n = 1777]. A significant association of heterozygous variant genotype in RAD54L with increased CSA frequency (OR 1.96, 95% CI 1.01-4.02, P = 0.03) was determined in 282 subjects with available genotype. By addressing gene-gene interactions, we discovered 14 interactions significantly modulating CAs, 9 CTAs and 12 CSAs frequencies. Highly significant interactions included always pairs from two different pathways. Although individual variants in genes encoding DNA repair proteins modulate CAs only modestly, several gene-gene interactions in DNA repair genes evinced either enhanced or decreased CA frequencies suggesting that CAs accumulation requires complex interplay between different DNA repair pathways.

• MeSH
• chromozomální aberace * MeSH
• DNA vazebné proteiny genetika   MeSH
• DNA-glykosylasy genetika   MeSH
• dospělí MeSH
• frekvence genu MeSH
• genetické asociační studie MeSH
• jednonukleotidový polymorfismus MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• nádory genetika   MeSH
• oprava DNA genetika   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

RESEARCH QUESTION: What is the incidence and origin of meiotic whole and segmental aneuploidies detected by karyomapping at a blastocyst stage in human-derived IVF embryos? What is the distribution of various types of errors, including rare chromosomal abnormalities? DESIGN: The incidence of chromosomal aneuploidies was assessed in 967 trophectoderm biopsies from 180 couples who underwent 215 cycles of IVF with preimplantation genetic testing for monogenetic disease with a known causal mutation with a mean maternal age of 32.7 years. DNA from both parents and a reference sample was genotyped together with the analysed trophectoderm samples by karyomapping (single-nucleotide-polymorphism-based array). RESULTS: Chromosomal abnormalities were detected in 31% of the analysed samples. At least one whole chromosomal aneuploidy was detected in 27.1% of the trophectoderm biopsies, whereas a segmental aneuploidy was detected in 5.1% of the trophectoderm biopsies. Our results reveal that segmental aneuploidies predominantly affect paternally derived chromosomes (70.4%; P < 0.01) compared with whole chromosomal aneuploidies that more frequently affect maternally derived chromosomes (90.1%; P < 0.0001). Also, the frequency of meiosis I (MI) and meiosis II (MII) errors was established in meiotic trisomies; MI errors were observed to be more frequent (n = 102/147 [69.4%]) than MII errors (n = 45/147 [30.6%]). CONCLUSIONS: Karyomapping is a robust method that is suitable for preimplantation genetic testing for monogenetic disease and for detecting meiotic aneuploidies, including meiotic segmental aneuploidies, and provides complex information about their parental origin. Our results revealed that segmental aneuploidy more frequently affects paternal chromosomes compared with whole chromosomal aneuploidy in human IVF embryos at the blastocyst stage.

• MeSH
• aneuploidie * MeSH
• chromozomální aberace * MeSH
• chromozomální poruchy epidemiologie   MeSH
• dospělí MeSH
• fertilizace in vitro * MeSH
• genetické testování MeSH
• incidence MeSH
• karyotypizace MeSH
• lidé MeSH
• meióza * MeSH
• preimplantační diagnóza metody   MeSH
• těhotenství MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Chromosomal translocations are acquired genetic rearrangements in human cancers. Jumping translocations are rare nonreciprocal rearrangements involving the same donor chromosome segment translocated to two or more recipient chromosomes. In this report, we describe a patient with Burkitt lymphoma/leukemia (BL) and a complex karyotype including a t(2;8)(p12;q24), copy-neutral loss of heterozygosity at 17p13.1-p13.3 and 19q13.1-q13.2, trisomy 20, and two uncommon chromosomal aberrations. The first uncommon aberration was a complex rearrangement of chromosome 15 (probably the consequence of chromothripsis) masked by an apparently balanced reciprocal translocation, t(11;15)(p11.2;q21). The second one was a special type of unbalanced "vice versa" jumping translocation, which involved the same acceptor chromosome arm (13q) and various donor chromosome segments. It is unclear whether both atypical rearrangements are the consequence of the TP53 alteration or whether assumed chromothripsis influenced the development of the jumping-like translocation. However, the presence of the t(11;15)(p11.2;q21) in all pathological cells suggests that it occurred in the early stage of the disease, whereas the jumping-like translocation, as an additional change, subsequently accelerated the progression of the disease.

• MeSH
• Burkittův lymfom diagnóza   genetika   MeSH
• chromozomální delece MeSH
• chromozomální poruchy genetika   MeSH
• dospělí MeSH
• lidé MeSH
• lidské chromozomy, pár 11 genetika   MeSH
• lidské chromozomy, pár 13 genetika   MeSH
• lidské chromozomy, pár 15 genetika   MeSH
• lidské chromozomy, pár 20 genetika   MeSH
• mozaicismus MeSH
• nádorový supresorový protein p53 genetika   MeSH
• translokace genetická * MeSH
• trizomie genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH

MDS with complex chromosomal aberrations (CCA) are characterized by short survival and a high rate of transformation to AML. A comprehensive genome-wide analysis of bone-marrow cells of 157 adults with newly diagnosed MDS and CCA revealed a large spectrum of nonrandom genomic changes related to the advanced stages of MDS. Chromosome shattering, probably resulting from chromothripsis, was found in 47% of patients. Deleted chromosome 5 was unstable and often involved in different types of cryptic unbalanced rearrangements. No true monosomy 5 was observed. Patients with CCA involving deleted chromosome 5 had an extremely poor prognosis (median overall survival, 2 months).

• MeSH
• chromozomální delece * MeSH
• dospělí MeSH
• karyotyp MeSH
• lidé středního věku MeSH
• lidé MeSH
• lidské chromozomy, pár 5 * MeSH
• myelodysplastické syndromy genetika   mortalita   MeSH
• prognóza MeSH
• retrospektivní studie MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• srovnávací genomová hybridizace 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
• časopisecké články MeSH
• práce podpořená grantem MeSH