• MeSH
• Clone Cells MeSH
• Chromosome Disorders MeSH
• Karyotyping MeSH
• Leukemia, Myeloid MeSH

• MeSH
• Biopsy methods   MeSH
• DNA, Neoplasm analysis   MeSH
• Carcinoma drug therapy   genetics   radiotherapy   MeSH
• Humans MeSH
• Breast Neoplasms drug therapy   genetics   radiotherapy   MeSH
• Flow Cytometry MeSH
• Check Tag
• Humans MeSH
• Publication type
• Comparative Study MeSH

Germline SAMD9 and SAMD9L mutations (SAMD9/9Lmut) predispose to myelodysplastic syndromes (MDS) with propensity for somatic rescue. In this study, we investigated a clinically annotated pediatric MDS cohort (n = 669) to define the prevalence, genetic landscape, phenotype, therapy outcome and clonal architecture of SAMD9/9L syndromes. In consecutively diagnosed MDS, germline SAMD9/9Lmut accounted for 8% and were mutually exclusive with GATA2 mutations present in 7% of the cohort. Among SAMD9/9Lmut cases, refractory cytopenia was the most prevalent MDS subtype (90%); acquired monosomy 7 was present in 38%; constitutional abnormalities were noted in 57%; and immune dysfunction was present in 28%. The clinical outcome was independent of germline mutations. In total, 67 patients had 58 distinct germline SAMD9/9Lmut clustering to protein middle regions. Despite inconclusive in silico prediction, 94% of SAMD9/9Lmut suppressed HEK293 cell growth, and mutations expressed in CD34+ cells induced overt cell death. Furthermore, we found that 61% of SAMD9/9Lmut patients underwent somatic genetic rescue (SGR) resulting in clonal hematopoiesis, of which 95% was maladaptive (monosomy 7 ± cancer mutations), and 51% had adaptive nature (revertant UPD7q, somatic SAMD9/9Lmut). Finally, bone marrow single-cell DNA sequencing revealed multiple competing SGR events in individual patients. Our findings demonstrate that SGR is common in SAMD9/9Lmut MDS and exemplify the exceptional plasticity of hematopoiesis in children.

• MeSH
• Single-Cell Analysis MeSH
• Bone Marrow Cells metabolism   MeSH
• Child MeSH
• HEK293 Cells MeSH
• Intracellular Signaling Peptides and Proteins genetics   MeSH
• Kaplan-Meier Estimate MeSH
• Clonal Evolution genetics   MeSH
• Clonal Hematopoiesis genetics   MeSH
• Infant MeSH
• Humans MeSH
• Adolescent MeSH
• Myelodysplastic Syndromes genetics   pathology   MeSH
• Tumor Suppressor Proteins genetics   MeSH
• Child, Preschool MeSH
• GATA2 Transcription Factor genetics   MeSH
• High-Throughput Nucleotide Sequencing MeSH
• Germ-Line Mutation genetics   MeSH
• Check Tag
• Child MeSH
• Infant MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH

Významným prognostickým faktorem u pacientů s chronickou lymfocytární leukemií je nález chromozomálních aberací. Jejich průkaz pomocí fluorescenční in situ hybridizace umožňuje rozdělit pacienty do prognostických skupin s rozdílným celkovým přežitím a intervalem od diagnózy do zahájení první terapie. Nález delece 17p je spojený s rezistencí na standardní chemoterapeutické režimy a průkaz této aberace může modifikovat léčebné rozhodnutí. Protože změny karyotypu nejsou stabilní po celou dobu onemocnění a v průběhu choroby může dojít ke klonální evoluci se vznikem nových aberací, je vhodné provádět cytogenetické vyšetření nejen při diagnóze, ale zvláště před zahájením každé linie léčby.

Chromosomal aberrations have important prognostic significance in patients with chronic lymphocytic leukemia. Aberrations detected by fluorescence in situ hybridization define specific subgroups that differ in the overall survival and the time from diagnosis to first treatment. Patients with deletion 17p appear resistant to standard chemotherapy regimens and detection of this cytogenetic abnormality may influence therapeutic decisions. Because additional genetic defects (clonal evolution) may be acquired during the course of the disease, cytogenetic analysis is recommended not only at diagnosis, but prior every line of the treatment.

• MeSH
• Survival Analysis MeSH
• Chromosome Aberrations classification   MeSH
• Leukemia, Lymphocytic, Chronic, B-Cell drug therapy   genetics   mortality   MeSH
• In Situ Hybridization, Fluorescence utilization   MeSH
• Humans MeSH
• Prognosis MeSH
• Gene Expression Regulation, Neoplastic MeSH
• Severity of Illness Index MeSH
• Check Tag
• Humans MeSH

Cancer development is a dynamic process during which the successive accumulation of mutations results in cells with increasingly malignant characteristics. Here, we show the clonal evolution pattern in myelodysplastic syndrome (MDS) patients receiving supportive care, with or without lenalidomide (follow-up 2.5-11 years). Whole-exome and targeted deep sequencing at multiple time points during the disease course reveals that both linear and branched evolutionary patterns occur with and without disease-modifying treatment. The application of disease-modifying therapy may create an evolutionary bottleneck after which more complex MDS, but also unrelated clones of haematopoietic cells, may emerge. In addition, subclones that acquired an additional mutation associated with treatment resistance (TP53) or disease progression (NRAS, KRAS) may be detected months before clinical changes become apparent. Monitoring the genetic landscape during the disease may help to guide treatment decisions.

• MeSH
• Bone Marrow Cells drug effects   metabolism   pathology   MeSH
• Drug Resistance, Neoplasm genetics   MeSH
• GTP Phosphohydrolases genetics   metabolism   MeSH
• Angiogenesis Inhibitors therapeutic use   MeSH
• Clonal Evolution drug effects   MeSH
• Lenalidomide MeSH
• Middle Aged MeSH
• Humans MeSH
• Disease Management MeSH
• Membrane Proteins genetics   metabolism   MeSH
• Monitoring, Physiologic MeSH
• Mutation MeSH
• Myelodysplastic Syndromes drug therapy   genetics   metabolism   pathology   MeSH
• Biomarkers, Tumor genetics   metabolism   MeSH
• Tumor Suppressor Protein p53 genetics   metabolism   MeSH
• Follow-Up Studies MeSH
• Disease Progression MeSH
• Proto-Oncogene Proteins p21(ras) genetics   metabolism   MeSH
• Gene Expression Regulation, Neoplastic * MeSH
• Exome Sequencing MeSH
• Aged MeSH
• Thalidomide analogs & derivatives   therapeutic use   MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Clonal growth of plants is attained by a number of morphologically different organs (e.g. stolons, rhizomes, and roots), which are not functionally equivalent. Consequently, these clonal growth organ (CGO) types can determine functional traits that are associated with clonality, although little is known about their evolutionary flexibility or the constraining role they play on clonal traits. We investigated the rates of evolutionary change by which individual CGOs are acquired and lost using a set of 2652 species of Central European flora. Furthermore, we asked how these individual CGOs constrain functionally relevant clonal traits, such as lateral spread, number of offspring, and persistence of connections. We show that plants can easily switch in evolution among individual types of CGO and between clonal and nonclonal habits. However, not all these transitions are equally probable. Namely, stem-based clonal growth and root-based clonal growth constitute evolutionarily separate forms of clonal growth. Clonal traits are strongly constrained by individual CGO types. Specifically, fast lateral spread is attained by stolons or hypogeogenous rhizomes, and persistent connections are attained by all rhizome types. However, the ease with which clonal organs appear and disappear in evolution implies that plants can overcome these constraints by adjusting their morphologies.

• MeSH
• Biological Evolution * MeSH
• Clone Cells MeSH
• Phylogeny MeSH
• Magnoliopsida growth & development   MeSH
• Organ Specificity MeSH
• Likelihood Functions MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Multiple myeloma (MM) is composed of an array of multiple clones, each potentially associated with different clinical behavior. Previous studies focused on clinical implication of centrosome amplification (CA) in MM show contradictory results. It seems that the role of CA as well as CA formation in MM differ from other malignancies. This has brought about a question about the role of CA positive clone which is--is it going to be a more aggressive clone evolutionally arising under pressure of negative conditions or can CA serve as a marker of cell abnormality and lead to cell death and further elimination of this damaged subpopulation? This current review is devoted to the discussion of the existence of MM subclones with centrosome amplification (CA), its evolutionary behaviour within intraclonal heterogeneity as well as its potential impact on the disease progression and MM treatment.

• MeSH
• Apoptosis physiology   MeSH
• Clone Cells MeSH
• Centrosome pathology   MeSH
• Stress, Physiological physiology   MeSH
• Carcinogenesis pathology   MeSH
• Clonal Evolution physiology   MeSH
• Humans MeSH
• Multiple Myeloma genetics   pathology   MeSH
• Disease Progression MeSH
• Cell Proliferation MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH

The karyotype of bone-marrow cells at the time of diagnosis is one of the most important prognostic factors in patients with myelodysplastic syndromes (MDS). In some cases, the acquisition of additional genetic aberrations (clonal evolution [CE]) associated with clinical progression may occur during the disease. We analyzed a cohort of 469 MDS patients using a combination of molecular cytogenomic methods to identify cryptic aberrations and to assess their potential role in CE. We confirmed CE in 36 (8%) patients. The analysis of bone-marrow samples with a combination of cytogenomic methods at diagnosis and after CE identified 214 chromosomal aberrations. The early genetic changes in the diagnostic samples were frequently MDS specific (17 MDS-specific/57 early changes). Most progression-related aberrations identified after CE were not MDS specific (131 non-MDS-specific/155 progression-related changes). Copy number neutral loss of heterozygosity (CN-LOH) was detected in 19% of patients. MDS-specific CN-LOH (4q, 17p) was identified in three patients, and probably pathogenic homozygous mutations were found in TET2 (4q24) and TP53 (17p13.1) genes. We observed a statistically significant difference in overall survival (OS) between the groups of patients divided according to their diagnostic cytogenomic findings, with worse OS in the group with complex karyotypes (P = .021). A combination of cytogenomic methods allowed us to detect many cryptic genomic changes and identify genes and genomic regions that may represent therapeutic targets in patients with progressive MDS.

• MeSH
• Survival Analysis MeSH
• Chromosome Aberrations MeSH
• DNA-Binding Proteins genetics   MeSH
• Adult MeSH
• Clonal Evolution * MeSH
• Middle Aged MeSH
• Humans MeSH
• Mutation MeSH
• Myelodysplastic Syndromes classification   genetics   pathology   MeSH
• Tumor Suppressor Protein p53 genetics   MeSH
• Prognosis MeSH
• Proto-Oncogene Proteins genetics   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Loss of Heterozygosity MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

In chronic lymphocytic leukemia (CLL), the worst prognosis is associated with TP53 defects with the affected patients being potentially directed to alternative treatment. Therapy administration was shown to drive the selection of new TP53 mutations in CLL. Using ultra-deep next-generation sequencing (NGS), we performed a detailed analysis of TP53 mutations' clonal evolution. We retrospectively analyzed samples that were assessed as TP53-wild-type (wt) by FASAY from 20 patients with a new TP53 mutation detected in relapse and 40 patients remaining TP53-wt in relapse. Minor TP53-mutated subclones were disclosed in 18/20 patients experiencing later mutation selection, while only one minor-clone mutation was observed in those patients remaining TP53-wt (n=40). We documented that (i) minor TP53 mutations may be present before therapy and may occur in any relapse; (ii) the majority of TP53-mutated minor clones expand to dominant clone under the selective pressure of chemotherapy, while persistence of minor-clone mutations is rare; (iii) multiple minor-clone TP53 mutations are common and may simultaneously expand. In conclusion, patients with minor-clone TP53 mutations carry a high risk of mutation selection by therapy. Deep sequencing can shift TP53 mutation identification to a period before therapy administration, which might be of particular importance for clinical trials.

• MeSH
• Survival Analysis MeSH
• Antineoplastic Agents administration & dosage   adverse effects   MeSH
• B-Lymphocytes drug effects   metabolism   pathology   MeSH
• Clone Cells MeSH
• Leukemia, Lymphocytic, Chronic, B-Cell drug therapy   genetics   mortality   pathology   MeSH
• Adult MeSH
• Clonal Evolution drug effects   genetics   MeSH
• Middle Aged MeSH
• Humans MeSH
• Mutation MeSH
• Tumor Suppressor Protein p53 genetics   metabolism   MeSH
• Recurrence MeSH
• Gene Expression Regulation, Leukemic * MeSH
• Retrospective Studies MeSH
• Aged MeSH
• Signal Transduction MeSH
• High-Throughput Nucleotide Sequencing MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Patients with chronic lymphocytic leukemia (CLL) bearing TP53 mutations experience chemorefractory disease and are therefore candidates for targeted therapy. However, the significance of low-burden TP53 mutations with <10% variant allele frequency (VAF) remains a matter for debate. Herein, we describe clonal evolution scenarios of low-burden TP53 mutations, the clinical impact of which we analyzed in a "real-world" CLL cohort. TP53 status was assessed by targeted next-generation sequencing (NGS) in 511 patients entering first-line treatment with chemo- and/or immunotherapy and 159 patients in relapse before treatment with targeted agents. Within the pretherapy cohort, 16% of patients carried low-burden TP53 mutations (0.1% to 10% VAF). Although their presence did not significantly shorten event-free survival after first-line therapy, it affected overall survival (OS). In a subgroup with TP53 mutations of 1% to 10% VAF, the impact on OS was observed only in patients with unmutated IGHV who had not received targeted therapy, as patients benefited from switching to targeted agents, regardless of initial TP53 mutational status. Analysis of the clonal evolution of low-burden TP53 mutations showed that the highest expansion rates were associated with fludarabine, cyclophosphamide, and rituximab regimen in both first- and second-line treatments (median VAF increase, 14.8× and 11.8×, respectively) in contrast to treatment with less intense treatment regimens (1.6×) and no treatment (0.8×). In the relapse cohort, 33% of patients carried low-burden TP53 mutations, which did not expand significantly upon targeted treatment (median VAF change, 1×). Sporadic cases of TP53 mutations' clonal shifts were connected with the development of resistance-associated mutations. Altogether, our data support the incorporation of low-burden TP53 variants in clinical decision making.

• MeSH
• Leukemia, Lymphocytic, Chronic, B-Cell genetics   therapy   MeSH
• Adult MeSH
• Immunotherapy MeSH
• Kaplan-Meier Estimate MeSH
• Clonal Evolution * drug effects   MeSH
• Middle Aged MeSH
• Humans MeSH
• Mutation drug effects   MeSH
• Tumor Cells, Cultured MeSH
• Tumor Suppressor Protein p53 genetics   MeSH
• Antineoplastic Combined Chemotherapy Protocols therapeutic use   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH