Our knowledge of genetic aberrations, that is, variants and copy number variations (CNVs), associated with mantle cell lymphoma (MCL) relapse remains limited. A cohort of 25 patients with MCL at diagnosis and the first relapse after the failure of standard immunochemotherapy was analyzed using whole-exome sequencing. The most frequent variants at diagnosis and at relapse comprised six genes: TP53, ATM, KMT2D, CCND1, SP140, and LRP1B. The most frequent CNVs at diagnosis and at relapse included TP53 and CDKN2A/B deletions, and PIK3CA amplifications. The mean count of mutations per patient significantly increased at relapse (n = 34) compared to diagnosis (n = 27). The most frequent newly detected variants at relapse, LRP1B gene mutations, correlated with a higher mutational burden. Variant allele frequencies of TP53 variants increased from 0.35 to 0.76 at relapse. The frequency and length of predicted CNVs significantly increased at relapse with CDKN2A/B deletions being the most frequent. Our data suggest, that the resistant MCL clones detected at relapse were already present at diagnosis and were selected by therapy. We observed enrichment of genetic aberrations of DNA damage response pathway (TP53 and CDKN2A/B), and a significant increase in MCL heterogeneity. We identified LRP1B inactivation as a new potential driver of MCL relapse.
- MeSH
- dospělí MeSH
- geny p16 MeSH
- klonální evoluce genetika MeSH
- lidé MeSH
- lokální recidiva nádoru MeSH
- lymfom z plášťových buněk * diagnóza farmakoterapie genetika MeSH
- variabilita počtu kopií segmentů DNA MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- MeSH
- cytogenetické vyšetření MeSH
- cytogenetika MeSH
- hematologické nádory * genetika MeSH
- hematologie * MeSH
- lidé MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- dopisy MeSH
- komentáře MeSH
Cytogenomic investigations of haematological neoplasms, including chromosome banding analysis, fluorescence in situ hybridisation (FISH) and microarray analyses have become increasingly important in the clinical management of patients with haematological neoplasms. The widespread implementation of these techniques in genetic diagnostics has highlighted the need for guidance on the essential criteria to follow when providing cytogenomic testing, regardless of choice of methodology. These recommendations provide an updated, practical and easily available document that will assist laboratories in the choice of testing and methodology enabling them to operate within acceptable standards and maintain a quality service.
- MeSH
- akutní myeloidní leukemie genetika MeSH
- chronická myeloidní leukemie MeSH
- hematologické nádory genetika MeSH
- hybridizace in situ fluorescenční MeSH
- lidé MeSH
- lymfom genetika MeSH
- mikročipová analýza MeSH
- mnohočetný myelom genetika MeSH
- myelodysplastické syndromy MeSH
- pruhování chromozomů MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- MeSH
- chronická lymfatická leukemie metabolismus mortalita patologie MeSH
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mikro RNA biosyntéza MeSH
- míra přežití MeSH
- následné studie MeSH
- přežití po terapii bez příznaků nemoci MeSH
- RNA nádorová biosyntéza MeSH
- senioři nad 80 let MeSH
- senioři 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
- dopisy MeSH
- práce podpořená grantem MeSH
We conducted a cytogenetic analysis of 642 children with de novo acute myeloid leukemia (AML) treated on the AML-Berlin-Frankfurt-Münster (BFM) 04 protocol to determine the prognostic value of specific chromosomal aberrations including monosomal (MK+), complex (CK+) and hypodiploid (HK+) karyotypes, individually and in combination. Multivariate regression analysis identified in particular MK+ (n=22) as a new independent risk factor for poor event-free survival (EFS 23±9% vs 53±2% for all other patients, P=0.0003), even after exclusion of four patients with monosomy 7 (EFS 28±11%, P=0.0081). CK+ patients without MK had a better prognosis (n=47, EFS 47±8%, P=0.46) than those with MK+ (n=12, EFS 25±13%, P=0.024). HK+ (n=37, EFS 44±8% for total cohort, P=0.3) influenced outcome only when t(8;21) patients were excluded (remaining n=16, EFS 9±8%, P<0.0001). An extremely poor outcome was observed for MK+/HK+ patients (n=10, EFS 10±10%, P<0.0001). Finally, isolated trisomy 8 was also associated with low EFS (n=16, EFS 25±11%, P=0.0091). In conclusion, monosomal karyotype is a strong and independent predictor for high-risk pediatric AML. In addition, isolated trisomy 8 and hypodiploidy without t(8;21) coincide with dismal outcome. These results have important implications for risk stratification and should be further validated in independent pediatric cohorts.
- MeSH
- akutní myeloidní leukemie diagnóza genetika mortalita MeSH
- analýza přežití MeSH
- chromozomální aberace MeSH
- genetická variace * MeSH
- genotyp * MeSH
- karyotyp MeSH
- klinické zkoušky jako téma MeSH
- lidé MeSH
- lidské chromozomy, pár 7 MeSH
- monozomie MeSH
- mutace MeSH
- prognóza MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Proximal 6q deletions have a milder phenotype than middle and distal 6q deletions. We describe 2 patients with non-overlapping deletions of about 15 and 19 Mb, respectively, which subdivide the proximal 6q region into 2 parts. The aberrations were identified using karyotyping and analysed using mBAND and array CGH. The unaffected mother of the first patient carried a mosaic karyotype with the deletion in all metaphases analysed and a small supernumerary marker formed by the deleted material in about 77% of cells. Her chromosome 6 centromeric signal was split between the deleted chromosome and the marker, suggesting that this deletion arose through the centromere fission mechanism. In this family the location of the proximal breakpoint in the centromere prevented cloning of the deletion junction, but the junction of the more distal deletion in the second patient was cloned and sequenced. This analysis showed that the latter aberration was most likely caused by non-homologous end joining. The second patient also had a remarkably more severe phenotype which could indicate a partial overlap of his deletion with the middle 6q interval. The phenotypes of both patients could be partly correlated with the gene content of their deletions and with phenotypes of other published patients.
- MeSH
- chromozomální delece MeSH
- fenotyp MeSH
- genetické asociační studie MeSH
- hybridizace in situ fluorescenční MeSH
- karyotyp MeSH
- kojenec MeSH
- lidé MeSH
- lidské chromozomy, pár 6 genetika MeSH
- předškolní dítě MeSH
- pruhování chromozomů MeSH
- srovnávací genomová hybridizace MeSH
- Check Tag
- kojenec MeSH
- lidé MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
- práce podpořená grantem MeSH
- Publikační typ
- abstrakt z konference MeSH
- MeSH
- chromozomální delece MeSH
- cytogenetické vyšetření MeSH
- dospělí MeSH
- finanční podpora výzkumu jako téma MeSH
- hybridizace in situ fluorescenční MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- myelodysplastické syndromy genetika klasifikace patologie MeSH
- prognóza MeSH
- refrakterní anemie genetika klasifikace MeSH
- senioři MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- senioři MeSH
- MeSH
- akutní monocytární leukemie genetika MeSH
- dospělí MeSH
- fúzní onkogenní proteiny genetika chemie klasifikace MeSH
- lidé MeSH
- lidské chromozomy, pár 16 genetika ultrastruktura MeSH
- messenger RNA genetika MeSH
- nádorové biomarkery genetika chemie MeSH
- polymerázová řetězová reakce MeSH
- zlomy chromozomů MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
