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Hematology. American Society of... Dec 2020Myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) overlap syndromes are uniquely classified neoplasms occurring in both children and adults. This category... (Review)
Review
Myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) overlap syndromes are uniquely classified neoplasms occurring in both children and adults. This category consists of 5 neoplastic subtypes: chronic myelomonocytic leukemia (CMML), juvenile myelomonocytic leukemia (JMML), BCR-ABL1-negative atypical chronic myeloid leukemia (aCML), MDS/MPN-ring sideroblasts and thrombocytosis (MDS/MPN-RS-T), and MDS/MPN-unclassifiable (U). Cytogenetic abnormalities and somatic copy number variations are uncommon; however, >90% patients harbor gene mutations. Although no single gene mutation is specific to a disease subtype, certain mutational signatures in the context of appropriate clinical and morphological features can be used to establish a diagnosis. In CMML, mutated coexpression of TET2 and SRSF2 results in clonal hematopoiesis skewed toward monocytosis, and the ensuing acquisition of driver mutations including ASXL1, NRAS, and CBL results in overt disease. MDS/MPN-RS-T demonstrates features of SF3B1-mutant MDS with ring sideroblasts (MDS-RS), with the development of thrombocytosis secondary to the acquisition of signaling mutations, most commonly JAK2V617F. JMML, the only pediatric entity, is a bona fide RASopathy, with germline and somatic mutations occurring in the oncogenic RAS pathway giving rise to disease. BCR-ABL1-negative aCML is characterized by dysplastic neutrophilia and is enriched in SETBP1 and ETNK1 mutations, whereas MDS/MPN-U is the least defined and lacks a characteristic mutational signature. Molecular profiling also provides prognostic information, with truncating ASXL1 mutations being universally detrimental and germline CBL mutations in JMML showing spontaneous regression. Sequencing information in certain cases can help identify potential targeted therapies (IDH1, IDH2, and splicing mutations) and should be a mainstay in the diagnosis and management of these neoplasms.
Topics: Aged; Chromosome Aberrations; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Genomics; Humans; Male; Mutation; Myelodysplastic Syndromes; Myelodysplastic-Myeloproliferative Diseases; Prognosis
PubMed: 33275756
DOI: 10.1182/hematology.2020000130 -
Nature Reviews. Molecular Cell Biology May 2020The tumour suppressor breast cancer type 1 susceptibility protein (BRCA1) promotes DNA double-strand break (DSB) repair by homologous recombination and protects DNA... (Review)
Review
The tumour suppressor breast cancer type 1 susceptibility protein (BRCA1) promotes DNA double-strand break (DSB) repair by homologous recombination and protects DNA replication forks from attrition. BRCA1 partners with BRCA1-associated RING domain protein 1 (BARD1) and other tumour suppressor proteins to mediate the initial nucleolytic resection of DNA lesions and the recruitment and regulation of the recombinase RAD51. The discovery of the opposing functions of BRCA1 and the p53-binding protein 1 (53BP1)-associated complex in DNA resection sheds light on how BRCA1 influences the choice of homologous recombination over non-homologous end joining and potentially other mutagenic pathways of DSB repair. Understanding the functional crosstalk between BRCA1-BARD1 and its cofactors and antagonists will illuminate the molecular basis of cancers that arise from a deficiency or misregulation of chromosome damage repair and replication fork maintenance. Such knowledge will also be valuable for understanding acquired tumour resistance to poly(ADP-ribose) polymerase (PARP) inhibitors and other therapeutics and for the development of new treatments. In this Review, we discuss recent advances in elucidating the mechanisms by which BRCA1-BARD1 functions in DNA repair, replication fork maintenance and tumour suppression, and its therapeutic relevance.
Topics: BRCA1 Protein; Breast Neoplasms; DNA End-Joining Repair; DNA Replication; Female; Humans; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Protein Binding; Recombinational DNA Repair; Tumor Suppressor Proteins; Tumor Suppressor p53-Binding Protein 1; Ubiquitin-Protein Ligases
PubMed: 32094664
DOI: 10.1038/s41580-020-0218-z -
American Journal of Human Genetics Aug 2021Chromosomal aberrations including structural variations (SVs) are a major cause of human genetic diseases. Their detection in clinical routine still relies on standard...
Chromosomal aberrations including structural variations (SVs) are a major cause of human genetic diseases. Their detection in clinical routine still relies on standard cytogenetics. Drawbacks of these tests are a very low resolution (karyotyping) and the inability to detect balanced SVs or indicate the genomic localization and orientation of duplicated segments or insertions (copy number variant [CNV] microarrays). Here, we investigated the ability of optical genome mapping (OGM) to detect known constitutional chromosomal aberrations. Ultra-high-molecular-weight DNA was isolated from 85 blood or cultured cells and processed via OGM. A de novo genome assembly was performed followed by structural variant and CNV calling and annotation, and results were compared to known aberrations from standard-of-care tests (karyotype, FISH, and/or CNV microarray). In total, we analyzed 99 chromosomal aberrations, including seven aneuploidies, 19 deletions, 20 duplications, 34 translocations, six inversions, two insertions, six isochromosomes, one ring chromosome, and four complex rearrangements. Several of these variants encompass complex regions of the human genome involved in repeat-mediated microdeletion/microduplication syndromes. High-resolution OGM reached 100% concordance compared to standard assays for all aberrations with non-centromeric breakpoints. This proof-of-principle study demonstrates the ability of OGM to detect nearly all types of chromosomal aberrations. We also suggest suited filtering strategies to prioritize clinically relevant aberrations and discuss future improvements. These results highlight the potential for OGM to provide a cost-effective and easy-to-use alternative that would allow comprehensive detection of chromosomal aberrations and structural variants, which could give rise to an era of "next-generation cytogenetics."
Topics: Chromosome Aberrations; Chromosome Disorders; Chromosome Mapping; Cytogenetic Analysis; DNA Copy Number Variations; Genome, Human; Humans; Karyotyping; Microarray Analysis
PubMed: 34237280
DOI: 10.1016/j.ajhg.2021.05.012 -
Proceedings of the National Academy of... May 2023The human tumor suppressor Ring finger protein 20 (RNF20)-mediated histone H2B monoubiquitination (H2Bub) is essential for proper chromosome segregation and DNA repair....
The human tumor suppressor Ring finger protein 20 (RNF20)-mediated histone H2B monoubiquitination (H2Bub) is essential for proper chromosome segregation and DNA repair. However, what is the precise function and mechanism of RNF20-H2Bub in chromosome segregation and how this pathway is activated to preserve genome stability remain unknown. Here, we show that the single-strand DNA-binding factor Replication protein A (RPA) interacts with RNF20 mainly in the S and G2/M phases and recruits RNF20 to mitotic centromeres in a centromeric R-loop-dependent manner. In parallel, RPA recruits RNF20 to chromosomal breaks upon DNA damage. Disruption of the RPA-RNF20 interaction or depletion of RNF20 increases mitotic lagging chromosomes and chromosome bridges and impairs BRCA1 and RAD51 loading and homologous recombination repair, leading to elevated chromosome breaks, genome instability, and sensitivities to DNA-damaging agents. Mechanistically, the RPA-RNF20 pathway promotes local H2Bub, H3K4 dimethylation, and subsequent SNF2H recruitment, ensuring proper Aurora B kinase activation at centromeres and efficient loading of repair proteins at DNA breaks. Thus, the RPA-RNF20-SNF2H cascade plays a broad role in preserving genome stability by coupling H2Bub to chromosome segregation and DNA repair.
Topics: Humans; Chromatin; Chromosome Segregation; DNA Repair; Genomic Instability; Histones; Homologous Recombination; Recombinational DNA Repair; Replication Protein A
PubMed: 37155876
DOI: 10.1073/pnas.2303479120 -
Blood Oct 2020More than 90% of patients with myelodysplastic/myeloproliferative neoplasms (MDSs/MPNs) harbor somatic mutations in myeloid-related genes, but still, current diagnostic...
More than 90% of patients with myelodysplastic/myeloproliferative neoplasms (MDSs/MPNs) harbor somatic mutations in myeloid-related genes, but still, current diagnostic criteria do not include molecular data. We performed genome-wide sequencing techniques to characterize the mutational landscape of a large and clinically well-characterized cohort including 367 adults with MDS/MPN subtypes, including chronic myelomonocytic leukemia (CMML; n = 119), atypical chronic myeloid leukemia (aCML; n = 71), MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T; n = 71), and MDS/MPN unclassifiable (MDS/MPN-U; n = 106). A total of 30 genes were recurrently mutated in ≥3% of the cohort. Distribution of recurrently mutated genes and clonal architecture differed among MDS/MPN subtypes. Statistical analysis revealed significant correlations between recurrently mutated genes, as well as genotype-phenotype associations. We identified specific gene combinations that were associated with distinct MDS/MPN subtypes and that were mutually exclusive with most of the other MDSs/MPNs (eg, TET2-SRSF2 in CMML, ASXL1-SETBP1 in aCML, and SF3B1-JAK2 in MDS/MPN-RS-T). Patients with MDS/MPN-U were the most heterogeneous and displayed different molecular profiles that mimicked the ones observed in other MDS/MPN subtypes and that had an impact on the outcome of the patients. Specific gene mutations also had an impact on the outcome of the different MDS/MPN subtypes, which may be relevant for clinical decision-making. Overall, the results of this study help to elucidate the heterogeneity found in these neoplasms, which can be of use in the clinical setting of MDS/MPN.
Topics: Aged; Aged, 80 and over; Alleles; Biomarkers; Bone Marrow; Chromosome Aberrations; Clonal Evolution; Clonal Hematopoiesis; Disease Susceptibility; Female; Genetic Predisposition to Disease; Genome-Wide Association Study; Genotype; Humans; Male; Middle Aged; Mutation; Myelodysplastic-Myeloproliferative Diseases; Phenotype; Prognosis; Exome Sequencing; Whole Genome Sequencing
PubMed: 32573691
DOI: 10.1182/blood.2019004229 -
Nature Aug 2021Reproductive longevity is essential for fertility and influences healthy ageing in women, but insights into its underlying biological mechanisms and treatments to...
Reproductive longevity is essential for fertility and influences healthy ageing in women, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.
Topics: Adult; Aging; Alleles; Animals; Bone and Bones; Checkpoint Kinase 1; Checkpoint Kinase 2; Diabetes Mellitus, Type 2; Diet; Europe; Asia, Eastern; Female; Fertility; Fragile X Mental Retardation Protein; Genetic Predisposition to Disease; Genome-Wide Association Study; Healthy Aging; Humans; Longevity; Menopause; Menopause, Premature; Mice; Mice, Inbred C57BL; Middle Aged; Ovary; Primary Ovarian Insufficiency; Uterus
PubMed: 34349265
DOI: 10.1038/s41586-021-03779-7 -
Cell Cycle (Georgetown, Tex.) Nov 2019Preservation and development of life depend on the adequate segregation of sister chromatids during mitosis and meiosis. This process is ensured by the cohesin... (Review)
Review
Preservation and development of life depend on the adequate segregation of sister chromatids during mitosis and meiosis. This process is ensured by the cohesin multi-subunit complex. Mutations in this complex have been associated with an increasing number of diseases, termed cohesinopathies. The best characterized cohesinopathy is Cornelia de Lange syndrome (CdLS), in which intellectual and growth retardations are the main phenotypic manifestations. Despite some overlap, the clinical manifestations of cohesinopathies vary considerably. Novel roles of the cohesin complex have emerged during the past decades, suggesting that important cell cycle regulators exert important biological effects through non-cohesion-related functions and broadening the potential pathomechanisms involved in cohesinopathies. This review focuses on non-cohesion-related functions of the cohesin complex, gene dosage effect, epigenetic regulation and TGF-β in cohesinopathy context, especially in comparison to hronic trial and ntestinal ysrhythmia (CAID) syndrome, a very distinct cohesinopathy caused by a homozygous Shugoshin-1 (SGO1) mutation (K23E) and characterized by pacemaker failure in both heart (sick sinus syndrome followed by atrial flutter) and gut (chronic intestinal pseudo-obstruction) with no intellectual or growth delay. We discuss the possible impact of SGO1 alterations in human pathologies and the potential impact of the SGO1 K23E mutation in the sinus node and gut development and functions. We suggest that the human phenotypes observed in CdLS, CAID syndrome and other cohesinopathies can inform future studies into the less well-known non-cohesion-related functions of cohesin complex genes. : AD: Alzheimer Disease; AFF4: AF4/FMR2 Family Member 4; ANKRD11: Ankyrin Repeat Domain 11; APC: Anaphase Promoter Complex; ASD: Atrial Septal Defect; ATRX: ATRX Chromatin Remodeler; ATRX: Alpha Thalassemia X-linked intellectual disability syndrome; BIRC5: Baculoviral IAP Repeat Containing 5; BMP: Bone Morphogenetic Protein; BRD4: Bromodomain Containing 4; BUB1: BUB1 Mitotic Checkpoint Serine/Threonine Kinase; CAID: Chronic Atrial and Intestinal Dysrhythmia; CDK1: Cyclin Dependent Kinase 1; CdLS: Cornelia de Lange Syndrome; CHD: Congenital Heart Disease; CHOPS: Cognitive impairment, coarse facies, Heart defects, Obesity, Pulmonary involvement, Short stature, and skeletal dysplasia; CIPO: Chronic Intestinal Pseudo-Obstruction; c-kit: KIT Proto-Oncogene Receptor Tyrosine Kinase; CoATs: Cohesin Acetyltransferases; CTCF: CCCTC-Binding Factor; DDX11: DEAD/H-Box Helicase 11; ERG: Transcriptional Regulator ERG; ESCO2: Establishment of Sister Chromatid Cohesion N-Acetyltransferase 2; GJC1: Gap Junction Protein Gamma 1; H2A: Histone H2A; H3K4: Histone H3 Lysine 4; H3K9: Histone H3 Lysine 9; HCN4: Hyperpolarization Activated Cyclic Nucleotide Gated Potassium and Sodium Channel 4;p HDAC8: Histone deacetylases 8; HP1: Heterochromatin Protein 1; ICC: Interstitial Cells of Cajal; ICC-MP: Myenteric Plexus Interstitial cells of Cajal; ICC-DMP: Deep Muscular Plexus Interstitial cells of Cajal; I: Pacemaker Funny Current; IP3: Inositol trisphosphate; JNK: C-Jun N-Terminal Kinase; LDS: Loeys-Dietz Syndrome; LOAD: Late-Onset Alzheimer Disease; MAPK: Mitogen-Activated Protein Kinase; MAU: MAU Sister Chromatid Cohesion Factor; MFS: Marfan Syndrome; NIPBL: NIPBL, Cohesin Loading Factor; OCT4: Octamer-Binding Protein 4; P38: P38 MAP Kinase; PDA: Patent Ductus Arteriosus; PDS5: PDS5 Cohesin Associated Factor; P-H3: Phospho Histone H3; PLK1: Polo Like Kinase 1; POPDC1: Popeye Domain Containing 1; POPDC2: Popeye Domain Containing 2; PP2A: Protein Phosphatase 2; RAD21: RAD21 Cohesin Complex Component; RBS: Roberts Syndrome; REC8: REC8 Meiotic Recombination Protein; RNAP2: RNA polymerase II; SAN: Sinoatrial node; SCN5A: Sodium Voltage-Gated Channel Alpha Subunit 5; SEC: Super Elongation Complex; SGO1: Shogoshin-1; SMAD: SMAD Family Member; SMC1A: Structural Maintenance of Chromosomes 1A; SMC3: Structural Maintenance of Chromosomes 3; SNV: Single Nucleotide Variant; SOX2: SRY-Box 2; SOX17: SRY-Box 17; SSS: Sick Sinus Syndrome; STAG2: Cohesin Subunit SA-2; TADs: Topology Associated Domains; TBX: T-box transcription factors; TGF-β: Transforming Growth Factor β; TGFBR: Transforming Growth Factor β receptor; TOF: Tetralogy of Fallot; TREK1: TREK-1 K(+) Channel Subunit; VSD: Ventricular Septal Defect; WABS: Warsaw Breakage Syndrome; WAPL: WAPL Cohesin Release Factor.
Topics: Animals; Atrial Flutter; Cell Cycle Proteins; Chromatids; Chromosomal Proteins, Non-Histone; Chromosome Segregation; De Lange Syndrome; Humans; Intestinal Pseudo-Obstruction; Mice; Mice, Inbred C57BL; Proto-Oncogene Mas; Sick Sinus Syndrome; Cohesins
PubMed: 31516082
DOI: 10.1080/15384101.2019.1658476 -
Orphanet Journal of Rare Diseases Jul 2022Turner syndrome (TS; ORPHA 881) is a rare condition in which all or part of one X chromosome is absent from some or all cells. It affects approximately one in every...
Turner syndrome (TS; ORPHA 881) is a rare condition in which all or part of one X chromosome is absent from some or all cells. It affects approximately one in every 1/2500 liveborn girls. The most frequently observed karyotypes are 45,X (40-50%) and the 45,X/46,XX mosaic karyotype (15-25%). Karyotypes with an X isochromosome (45,X/46,isoXq or 45,X/46,isoXp), a Y chromosome, X ring chromosome or deletions of the X chromosome are less frequent. The objective of the French National Diagnosis and Care Protocol (PNDS; Protocole National de Diagnostic et de Soins) is to provide health professionals with information about the optimal management and care for patients, based on a critical literature review and multidisciplinary expert consensus. The PNDS, written by members of the French National Reference Center for Rare Growth and Developmental Endocrine disorders, is available from the French Health Authority website. Turner Syndrome is associated with several phenotypic conditions and a higher risk of comorbidity. The most frequently reported features are growth retardation with short adult stature and gonadal dysgenesis. TS may be associated with various congenital (heart and kidney) or acquired diseases (autoimmune thyroid disease, celiac disease, hearing loss, overweight/obesity, glucose intolerance/type 2 diabetes, dyslipidemia, cardiovascular complications and liver dysfunction). Most of the clinical traits of TS are due to the haploinsufficiency of various genes on the X chromosome, particularly those in the pseudoautosomal regions (PAR 1 and PAR 2), which normally escape the physiological process of X inactivation, although other regions may also be implicated. The management of patients with TS requires collaboration between several healthcare providers. The attending physician, in collaboration with the national care network, will ensure that the patient receives optimal care through regular follow-up and screening. The various elements of this PNDS are designed to provide such support.
Topics: Adult; Chromosomes, Human, X; Diabetes Mellitus, Type 2; Female; Humans; Karyotype; Karyotyping; Turner Syndrome
PubMed: 35821070
DOI: 10.1186/s13023-022-02423-5 -
Molecular Cytogenetics Jun 2022Structural chromosomal rearrangements result from different mechanisms of formation, usually related to certain genomic architectural features that may lead to genetic... (Review)
Review
Structural chromosomal rearrangements result from different mechanisms of formation, usually related to certain genomic architectural features that may lead to genetic instability. Most of these rearrangements arise from recombination, repair, or replication mechanisms that occur after a double-strand break or the stalling/breakage of a replication fork. Here, we review the mechanisms of formation of structural rearrangements, highlighting their main features and differences. The most important mechanisms of constitutional chromosomal alterations are discussed, including Non-Allelic Homologous Recombination (NAHR), Non-Homologous End-Joining (NHEJ), Fork Stalling and Template Switching (FoSTeS), and Microhomology-Mediated Break-Induced Replication (MMBIR). Their involvement in chromoanagenesis and in the formation of complex chromosomal rearrangements, inverted duplications associated with terminal deletions, and ring chromosomes is also outlined. We reinforce the importance of high-resolution analysis to determine the DNA sequence at, and near, their breakpoints in order to infer the mechanisms of formation of structural rearrangements and to reveal how cells respond to DNA damage and repair broken ends.
PubMed: 35701783
DOI: 10.1186/s13039-022-00600-6