ABSTRACT
Dermatofibrosarcoma protuberans (DFSP) is a rare sarcoma of the skin arising from the dermis. Its location is most commonly presented on the trunk of middle-aged adults and rarely on the face. The characteristic genetic aberration in the form of a reciprocal translocation t(17;22)(q21;q13) or a ring fusing the COL1A1 and PDGFB genes is found in 90% of DFSP. We present a case of a 42-year-old man who presented with a DFSP on the left cheek with foci of myxoid-fibrosarcomatous transformation. A conventional chromosomal analysis revealed a complex karyotype without a supernumerary ring chromosome or a linear translocation t(17;22). Comparative genome hybridization and fluorescence in-situ hybridization revealed the fusion of COL1A1 and PDGFB probes inserted in chromosome 15. This is a unique case of DFSP characterized by a rare body location, unique histopathological features, and novel chromosome COL1A1-PDGFB insertion, and may help guide future diagnostic and patient care modalities.
Subject(s)
Chromosomes, Human, Pair 15 , Facial Neoplasms , Fibrosarcoma , Mutagenesis, Insertional , Oncogene Proteins, Fusion , Skin Neoplasms , Adult , Chromosomes, Human, Pair 15/genetics , Chromosomes, Human, Pair 15/metabolism , Chromosomes, Human, Pair 17/genetics , Chromosomes, Human, Pair 17/metabolism , Chromosomes, Human, Pair 22/genetics , Chromosomes, Human, Pair 22/metabolism , Facial Neoplasms/genetics , Facial Neoplasms/metabolism , Facial Neoplasms/pathology , Fibrosarcoma/genetics , Fibrosarcoma/metabolism , Fibrosarcoma/pathology , Humans , Male , Oncogene Proteins, Fusion/genetics , Oncogene Proteins, Fusion/metabolism , Skin Neoplasms/genetics , Skin Neoplasms/metabolism , Skin Neoplasms/pathology , Translocation, GeneticSubject(s)
Bridged Bicyclo Compounds, Heterocyclic/administration & dosage , Chromosome Deletion , Chromosomes, Human, Pair 13/genetics , Leukemia, Lymphocytic, Chronic, B-Cell , Rituximab/administration & dosage , Smith-Magenis Syndrome , Sulfonamides/administration & dosage , Tumor Suppressor Protein p53/genetics , Aged , Chromosomes, Human, Pair 17/genetics , Chromosomes, Human, Pair 17/metabolism , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/metabolism , Male , Recurrence , Smith-Magenis Syndrome/drug therapy , Smith-Magenis Syndrome/genetics , Smith-Magenis Syndrome/metabolism , Smith-Magenis Syndrome/pathologyABSTRACT
OBJECTIVE: Dual probe fluorescence in situ hybridization (FISH) assays for determination of human epidermal growth factor receptor 2 (HER2) gene amplification in breast cancer provide a ratio of HER2 to chromosome 17. The ratio may be skewed by copy number alterations (CNA) in the control locus for chromosome 17 (CEP17). We analyzed the impact of alternative chromosome 17 control probes on HER2 status in a series of breast cancers with an emphasis on patients reclassified as amplified. METHODS: Breast cancer patients with equivocal HER2 immunohistochemistry (2+) and equivocal FISH with CEP17 were included. Reclassification of HER2 status was assessed with alternative chromosome 17 control probes (LIS1 and RARA). RESULTS: A total of 40 unique patients with 46 specimens reflexed to alternative chromosome 17 probe testing were identified. The majority (>80%) of patients had pT1-2, hormone receptor-positive tumors with an intermediate or high combined histologic grade. There were 34/46 (73.9%) specimens reclassified as amplified with alternative probes, corresponding to 29/40 (72.5%) patients. Of the patients reclassified as amplified with alternative probes, 34.5% (10/29) received HER2-targeted therapy. CONCLUSION: In this series, the majority of breast cancers tested with alternative chromosome 17 control probes under the 2013 ASCO/CAP Guidelines were converted to HER2-amplified. The treatment data and the clinicopathologic profile of the tumors suggest that most of these patients will neither receive nor benefit from HER2-targeted therapy. The findings support the recommendation in the 2018 ASCO/CAP HER2 Guidelines to discontinue the use of alternative chromosome 17 probes.
Subject(s)
Breast Neoplasms/pathology , Chromosomes, Human, Pair 17/metabolism , In Situ Hybridization, Fluorescence/methods , Receptor, ErbB-2/metabolism , Adult , Aged , Aged, 80 and over , Antineoplastic Agents, Immunological/metabolism , Antineoplastic Agents, Immunological/therapeutic use , Biomarkers, Tumor/genetics , Breast Neoplasms/classification , Breast Neoplasms/metabolism , Breast Neoplasms/therapy , DNA Copy Number Variations/genetics , Female , Humans , Medical Oncology/organization & administration , Middle Aged , Molecular Targeted Therapy/statistics & numerical data , Neoplasm Grading/methods , Practice Guidelines as Topic , Retrospective Studies , Societies, Medical/organization & administration , Trastuzumab/metabolism , Trastuzumab/therapeutic use , United StatesABSTRACT
Breast cancer is the most commonly diagnosed neoplasm in women worldwide with a well-recognized heterogeneous pathology, classified into four molecular subtypes: Luminal A, Luminal B, HER2-enriched and Basal-like, each one with different biological and clinical characteristics. Long non-coding RNAs (lncRNAs) represent 33% of the human transcriptome and play critical roles in breast carcinogenesis, but most of their functions are still unknown. Therefore, cancer research could benefit from continued exploration into the biology of lncRNAs in this neoplasm. We characterized lncRNA expression portraits in 74 breast tumors belonging to the four molecular subtypes using transcriptome microarrays. To infer the biological role of the deregulated lncRNAs in the molecular subtypes, we performed co-expression analysis of lncRNA-mRNA and gene ontology analysis. We identified 307 deregulated lncRNAs in tumor compared to normal tissue and 354 deregulated lncRNAs among the different molecular subtypes. Through co-expression analysis between lncRNAs and protein-coding genes, along with gene enrichment analysis, we inferred the potential function of the most deregulated lncRNAs in each molecular subtype, and independently validated our results taking advantage of TCGA data. Overexpression of the AC009283.1 was observed in the HER2-enriched subtype and it is localized in an amplification zone at chromosome 17q12, suggesting it to be a potential tumorigenic lncRNA. The functional role of lncRNA AC009283.1 was examined through loss of function assays in vitro and determining its impact on global gene expression. These studies revealed that AC009283.1 regulates genes involved in proliferation, cell cycle and apoptosis in a HER2 cellular model. We further confirmed these findings through ssGSEA and CEMITool analysis in an independent HER2-amplified breast cancer cohort. Our findings suggest a wide range of biological functions for lncRNAs in each breast cancer molecular subtype and provide a basis for their biological and functional study, as was conducted for AC009283.1, showing it to be a potential regulator of proliferation and apoptosis in the HER2-enriched subtype.
Subject(s)
Apoptosis , Breast Neoplasms/metabolism , Cell Proliferation , Chromosomes, Human, Pair 17 , RNA, Long Noncoding/biosynthesis , Receptor, ErbB-2/metabolism , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Chromosomes, Human, Pair 17/genetics , Chromosomes, Human, Pair 17/metabolism , Female , Humans , MCF-7 Cells , RNA, Long Noncoding/genetics , Receptor, ErbB-2/geneticsABSTRACT
Risk for childhood asthma is conferred by alleles within the 17q21 locus affecting ORMDL sphingolipid biosynthesis regulator 3 (ORMDL3) expression. ORMDL3 inhibits sphingolipid de novo synthesis. Although the effects of 17q21 genotypes on sphingolipid synthesis in human asthma remain unclear, both decreased sphingolipid synthesis and ORMDL3 overexpression are linked to airway hyperreactivity. To characterize the relationship of genetic asthma susceptibility with sphingolipid synthesis, we analyzed asthma-associated 17q21 genotypes (rs7216389, rs8076131, rs4065275, rs12603332, and rs8067378) in both children with asthma and those without asthma, quantified plasma and whole-blood sphingolipids, and assessed sphingolipid de novo synthesis in peripheral blood cells by measuring the incorporation of stable isotope-labeled serine (substrate) into sphinganine and sphinganine-1-phosphate. Whole-blood dihydroceramides and ceramides were decreased in subjects with the 17q21 asthma-risk alleles rs7216389 and rs8076131. Children with nonallergic asthma had lower dihydroceramides, ceramides, and sphingomyelins than did controls. Children with allergic asthma had higher dihydroceramides, ceramides, and sphingomyelins compared with children with nonallergic asthma. Additionally, de novo sphingolipid synthesis was lower in children with asthma compared with controls. These findings connect genetic 17q21 variations that are associated with asthma risk and higher ORMDL3 expression to lower sphingolipid synthesis in humans. Altered sphingolipid synthesis may therefore be a critical factor in asthma pathogenesis and may guide the development of future therapeutics.
Subject(s)
Asthma , Chromosomes, Human, Pair 17 , Genetic Diseases, Inborn , Membrane Proteins , Sphingolipids/biosynthesis , Adolescent , Asthma/blood , Asthma/genetics , Asthma/pathology , Case-Control Studies , Child , Child, Preschool , Chromosomes, Human, Pair 17/genetics , Chromosomes, Human, Pair 17/metabolism , Female , Genetic Diseases, Inborn/blood , Genetic Diseases, Inborn/genetics , Genetic Diseases, Inborn/pathology , Humans , Male , Membrane Proteins/blood , Membrane Proteins/genetics , Risk FactorsABSTRACT
Pigmented epithelioid melanocytoma (PEM) represents a group of rare, heavily pigmented melanocytic tumors encompassing lesions previously designated as "animal-type melanomas" and "epithelioid blue nevi." Despite the association of multiple such tumors in the setting of Carney complex, most cases of PEM occur spontaneously as solitary neoplasms in otherwise healthy patients. PEM may arise in both children and adults, and has a known propensity to spread to the regional lymph nodes. Despite this latter finding, recurrence at the biopsy site or spread beyond the lymph node basin is exceptionally uncommon. Although the molecular basis for PEM continues to be characterized, findings to date suggest that this category of melanocytic neoplasia has genetic alterations distinct from those seen in common nevi, dysplastic nevi, Spitz nevi, and melanoma. Herein, we present an in-depth clinical, histopathologic, and molecular analysis of a case of PEM occurring on the scalp of a young African American girl found to have a novel NTRK3-SCAPER gene fusion.
Subject(s)
Carrier Proteins , Chromosome Aberrations , Chromosomes, Human, Pair 15 , Chromosomes, Human, Pair 17 , Discoidin Domain Receptor 2 , Head and Neck Neoplasms , Nevus, Blue , Oncogene Proteins, Fusion , Carrier Proteins/genetics , Carrier Proteins/metabolism , Child, Preschool , Chromosomes, Human, Pair 15/genetics , Chromosomes, Human, Pair 15/metabolism , Chromosomes, Human, Pair 17/genetics , Chromosomes, Human, Pair 17/metabolism , Discoidin Domain Receptor 2/genetics , Discoidin Domain Receptor 2/metabolism , Female , Head and Neck Neoplasms/genetics , Head and Neck Neoplasms/metabolism , Head and Neck Neoplasms/pathology , Humans , Nevus, Blue/genetics , Nevus, Blue/metabolism , Skin Neoplasms/genetics , Skin Neoplasms/metabolism , Skin Neoplasms/pathologyABSTRACT
Limited data are available on the incidence and impact of TP53 alterations and TP53 pathway deregulation in paediatric acute myeloid leukaemia (AML). We analysed TP53 alterations in bone marrow samples of 229 patients with de novo paediatric AML, and detected heterozygous missense exon mutations in two patients (1%) and 17p deletions of the TP53 gene in four patients (2%). These patients more frequently had complex karyotype (50% vs. 4%, P = 0·002) or adverse cytogenetic abnormalities, including complex karyotype (67% vs. 17%, P = 0·013), compared to TP53 wild-type. Differential expression of TP53 pathway genes was associated with poor survival, indicating a role for TP53 regulators and effector genes.
Subject(s)
Chromosome Deletion , Gene Expression Regulation, Leukemic , Leukemia, Myeloid, Acute , Mutation , Signal Transduction , Smith-Magenis Syndrome , Tumor Suppressor Protein p53 , Adolescent , Child , Child, Preschool , Chromosomes, Human, Pair 17/genetics , Chromosomes, Human, Pair 17/metabolism , Disease-Free Survival , Female , Humans , Infant , Infant, Newborn , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/metabolism , Leukemia, Myeloid, Acute/mortality , Male , Smith-Magenis Syndrome/genetics , Smith-Magenis Syndrome/metabolism , Smith-Magenis Syndrome/mortality , Survival Rate , Tumor Suppressor Protein p53/biosynthesis , Tumor Suppressor Protein p53/geneticsABSTRACT
Primary thyroid teratomas are rare, usually benign, and typically occur in children. We report the unusual occurrence of a malignant thyroid teratoma in a young man. Initial ultrasound and CT studies revealed an 8.5 heterogeneous mass involving the entire right thyroid lobe causing tracheal compression and deviation. Fine-needle aspiration (FNA) revealed malignant cells with possible neuroendocrine features. Similar findings have been previously reported, with an occasional interpretation as possible medullary thyroid carcinoma. In no report, as with our case, has the correct diagnosis been suggested with FNA. The surgical specimen contained abundant primitive neuroepithelium with a very minor component of mature ectodermal tissue in one area. Like this case, an abundance of immature neuroepithelium has been reported in essentially all previous reports of primary malignant thyroid teratoma, sometimes creating a challenge to find another type of germ cell tissue. Array comparative genomic hybridization studies in this case revealed a markedly complex karyotype including gain of chromosome 12 and loss of 17p. Amplification of MYCN, EWSR1 rearrangement and isochromosome 12p were not identified, providing no evidence for neuroblastoma or Ewing sarcoma/peripheral neuroectodermal tumor, both of which have also rarely been reported as primary thyroid tumors. With the use of cisplatinum-based chemotherapy combined with radiation, survival times have increased dramatically. Our patient is now disease free and back to his normal activities after relatively short follow-up. Although rare, it is important to be aware that teratomas may present as a thyroid nodule. Recognition by FNA is challenging, and requires multiple modalities for full identification.
Subject(s)
Chemoradiotherapy , Cisplatin/administration & dosage , Teratoma , Thyroid Neoplasms , Adolescent , Biopsy, Fine-Needle , Chromosome Deletion , Chromosomes, Human, Pair 12/genetics , Chromosomes, Human, Pair 12/metabolism , Chromosomes, Human, Pair 17/genetics , Chromosomes, Human, Pair 17/metabolism , Humans , Male , N-Myc Proto-Oncogene Protein/genetics , N-Myc Proto-Oncogene Protein/metabolism , RNA-Binding Protein EWS/genetics , RNA-Binding Protein EWS/metabolism , Smith-Magenis Syndrome/genetics , Smith-Magenis Syndrome/metabolism , Smith-Magenis Syndrome/pathology , Smith-Magenis Syndrome/therapy , Teratoma/genetics , Teratoma/metabolism , Teratoma/pathology , Teratoma/therapy , Thyroid Neoplasms/genetics , Thyroid Neoplasms/metabolism , Thyroid Neoplasms/pathology , Thyroid Neoplasms/therapyABSTRACT
BACKGROUND: HER-2 and TOP2A genes are considered of great importance in breast cancer. Their copy number variability has been proposed to be a marker for the degree of chromosomal instability. Owing to the close proximity of TOP2A gene to HER-2 gene chromosome 17, TOP2A status is believed to affect therapeutic plan. The percentage of TOP2A aberrations is greatly variable among different studies. AIM OF WORK: Is to investigate the relation between TOP2A and HER-2 gene amplification using fluorescence in situ hybridization technique. MATERIALS AND METHODS: Archival blocks of 112 breast cancer Egyptian female patients were retrieved from the pathology department at NCI, Cairo University were retrieved and investigated using fluorescence in situ hybridization technique for TOP2A and HER-2 gene assessment. In addition, correlation with some clinicopathologic parameters was done. RESULTS: HER-2 gene amplification was encountered in about 33% of cases. TOP2A gene amplification and deletion were detected in 23.9% and 2.8% of studied cases. Moderate agreement was obtained between results of HER-2 gene and TOP2A gene amplification. CONCLUSIONS: HER-2 and TOP2A genes amplification are 2 separate genetic yet closely related events in breast cancer. Polysomy of chromosome 17 is proposed to be an early event in occurrence of TOP2A gene amplification. Further studies regarding effect of TOP2A gene in response to anthracyclines in Egyptian population should be planned for to establish its role in therapeutic planning.
Subject(s)
Breast Neoplasms , Chromosomes, Human, Pair 17 , DNA Topoisomerases, Type II , Gene Amplification , In Situ Hybridization, Fluorescence , Poly-ADP-Ribose Binding Proteins , Receptor, ErbB-2 , Adult , Aged , Aged, 80 and over , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Chromosomes, Human, Pair 17/genetics , Chromosomes, Human, Pair 17/metabolism , DNA Topoisomerases, Type II/genetics , DNA Topoisomerases, Type II/metabolism , Egypt , Female , Humans , Middle Aged , Poly-ADP-Ribose Binding Proteins/genetics , Poly-ADP-Ribose Binding Proteins/metabolism , Receptor, ErbB-2/genetics , Receptor, ErbB-2/metabolism , Retrospective StudiesSubject(s)
Chromosomes, Human, Pair 17/genetics , Leukemia, Promyelocytic, Acute , Mutagenesis, Insertional , Oncogene Proteins, Fusion , Adult , Chromosomes, Human, Pair 17/metabolism , Female , Humans , Leukemia, Promyelocytic, Acute/genetics , Leukemia, Promyelocytic, Acute/metabolism , Oncogene Proteins, Fusion/biosynthesis , Oncogene Proteins, Fusion/geneticsABSTRACT
The aim of this study was to investigate long-term outcome following first-line therapy in consecutive chronic lymphocytic leukemia (CLL) patients in a well-defined geographic area: Sweden. All patients diagnosed with CLL (2007-2013) (n=3672) were identified from national registries, screening of patient files identified all (100%) treated first line (n=1053) and for those, an in-depth analysis was performed. End points were overall response rate, progression-free survival (PFS), overall survival (OS), and safety. Median age was 71 years; 53% had Rai stage III-IV and 97% had performance status grade 0-2. Fluorescence in situ hybridization (FISH) was performed in 57% of patients: 15% had del(17p). Chlorambucil + prednisone was used in 39% (5% also received rituximab). Fludarabine+cyclophosphamide+rituximab or fludarabine+cyclophosphamide was used in 43% and bendamustine + rituximab in 6%. Overall response rate was 64%; chlorambucil 43%, fludarabine+cyclophosphamide+rituximab 84%, fludarabine+cyclophosphamide 75% and bendamustine + rituximab 75%. Median PFS and OS was 24 and 58 months, respectively, both were significantly associated (multivariate analysis) with type of treatment, del(17p), performance status, gender, age and geographical region (OS only). Chlorambucil-treated patients had a median PFS and OS of only 9 and 33 months, respectively. Chlorambucil usage declined gradually throughout the study period, but one-third of patients still received chlorambucil + rituximab in 2013. Infections ≥grade III were significantly associated with treatment; chlorambucil 19% versus fludarabine+cyclophosphamide+rituximab 30%. Richter transformation occurred in 5.5% of the patients, equally distributed across therapies. This is the largest retrospective, real-world cohort of consecutive first-line treated CLL patients with a complete follow up. In elderly patients, an unmet need for more effective, well-tolerated therapies was identified.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Leukemia, Lymphocytic, Chronic, B-Cell , Registries , Adult , Aged , Aged, 80 and over , Bendamustine Hydrochloride/administration & dosage , Chlorambucil/administration & dosage , Chromosome Deletion , Chromosomes, Human, Pair 17/genetics , Chromosomes, Human, Pair 17/metabolism , Cyclophosphamide/administration & dosage , Disease-Free Survival , Female , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/metabolism , Leukemia, Lymphocytic, Chronic, B-Cell/mortality , Male , Middle Aged , Prednisolone/administration & dosage , Retrospective Studies , Rituximab/administration & dosage , Survival Rate , Sweden/epidemiology , Vidarabine/administration & dosage , Vidarabine/analogs & derivativesABSTRACT
Heterozygous deletion of chromosome 17p (17p) is one of the most frequent genomic events in human cancers. Beyond the tumor suppressor TP53, the POLR2A gene encoding the catalytic subunit of RNA polymerase II (RNAP2) is also included in a ~20-megabase deletion region of 17p in 63% of metastatic castration-resistant prostate cancer (CRPC). Using a focused CRISPR-Cas9 screen, we discovered that heterozygous loss of 17p confers a selective dependence of CRPC cells on the ubiquitin E3 ligase Ring-Box 1 (RBX1). RBX1 activates POLR2A by the K63-linked ubiquitination and thus elevates the RNAP2-mediated mRNA synthesis. Combined inhibition of RNAP2 and RBX1 profoundly suppress the growth of CRPC in a synergistic manner, which potentiates the therapeutic effectivity of the RNAP2 inhibitor, α-amanitin-based antibody drug conjugate (ADC). Given the limited therapeutic options for CRPC, our findings identify RBX1 as a potentially therapeutic target for treating human CRPC harboring heterozygous deletion of 17p.
Subject(s)
Chromosomes, Human, Pair 17/metabolism , Prostatic Neoplasms, Castration-Resistant/metabolism , RNA Polymerase II/metabolism , Apoptosis/genetics , Apoptosis/physiology , Carrier Proteins/genetics , Carrier Proteins/metabolism , Cell Line, Tumor , Cell Survival/genetics , Cell Survival/physiology , Chromosomes, Human, Pair 17/genetics , Humans , Immunoblotting , Immunohistochemistry , Immunoprecipitation , Male , Prostatic Neoplasms, Castration-Resistant/genetics , RNA Polymerase II/genetics , Sequence Deletion/genetics , Sequence Deletion/physiology , Transcription, Genetic/genetics , Transcription, Genetic/physiology , Ubiquitin-Protein LigasesSubject(s)
Gene Expression Regulation, Leukemic , Leukemia, Promyelocytic, Acute , Oncogene Proteins, Fusion , PPAR gamma , mRNA Cleavage and Polyadenylation Factors , Adult , Chromosomes, Human, Pair 15/genetics , Chromosomes, Human, Pair 15/metabolism , Chromosomes, Human, Pair 17/genetics , Chromosomes, Human, Pair 17/metabolism , Humans , Leukemia, Promyelocytic, Acute/genetics , Leukemia, Promyelocytic, Acute/metabolism , Leukemia, Promyelocytic, Acute/pathology , Male , Oncogene Proteins, Fusion/biosynthesis , Oncogene Proteins, Fusion/genetics , PPAR gamma/biosynthesis , PPAR gamma/genetics , Translocation, Genetic , mRNA Cleavage and Polyadenylation Factors/biosynthesis , mRNA Cleavage and Polyadenylation Factors/geneticsSubject(s)
Intellectual Disability/genetics , Smith-Magenis Syndrome/genetics , Smith-Magenis Syndrome/metabolism , Child , Chromosome Deletion , Chromosomes, Human, Pair 11/genetics , Chromosomes, Human, Pair 17/genetics , Chromosomes, Human, Pair 17/metabolism , Genetic Association Studies , Humans , Male , PhenotypeABSTRACT
Naxos disease, first described by Dr. Nikos Protonotarios and colleagues on the island of Naxos, Greece, is a special form of arrhythmogenic right ventricular dysplasia (ARVD). It is an inherited condition with a recessive form of transmission and a familial penetrance of 90%. It is associated with thickening of the skin of the hands and sole, and a propensity to woolly hair. The cardiac anomalies characterized by ventricular arrhythmias with ventricular extrasystoles and tachycardia and histologic features of the myocardium are consistent with ARVD, but in a more severe form of dysplasia with major dilatation of the right ventricle. The identification of the responsible first gene on chromosome 17, and its product plakoglobin as the responsible protein for Naxos disease proved to be a milestone in the study of ARVD, which opened a new field of research. Thanks to those with the determination to discover Naxos disease, there is and will be more clarity in understanding the mechanisms of juvenile sudden death in the young who have an apparently otherwise normal heart.
Subject(s)
Arrhythmogenic Right Ventricular Dysplasia/physiopathology , Hair Diseases/physiopathology , Keratoderma, Palmoplantar/physiopathology , Animals , Arrhythmogenic Right Ventricular Dysplasia/genetics , Arrhythmogenic Right Ventricular Dysplasia/mortality , Arrhythmogenic Right Ventricular Dysplasia/pathology , Chromosomes, Human, Pair 17/genetics , Chromosomes, Human, Pair 17/metabolism , Death, Sudden , Hair Diseases/genetics , Hair Diseases/mortality , Hair Diseases/pathology , Humans , Keratoderma, Palmoplantar/genetics , Keratoderma, Palmoplantar/mortality , Keratoderma, Palmoplantar/pathology , gamma Catenin/genetics , gamma Catenin/metabolismABSTRACT
We propose a new computational method for exploring chromatin structural organization based on Markov State Modelling of Hi-C data represented as an interaction network between genomic loci. A Markov process describes the random walk of a traveling probe in the corresponding energy landscape, mimicking the motion of a biomolecule involved in chromatin function. By studying the metastability of the associated Markov State Model upon annealing, the hierarchical structure of individual chromosomes is observed, and corresponding set of structural partitions is identified at each level of hierarchy. Then, the notion of effective interaction between partitions is derived, delineating the overall topology and architecture of chromosomes. Mapping epigenetic data on the graphs of intra-chromosomal effective interactions helps in understanding how chromosome organization facilitates its function. A sketch of whole-genome interactions obtained from the analysis of 539 partitions from all 23 chromosomes, complemented by distributions of gene expression regulators and epigenetic factors, sheds light on the structure-function relationships in chromatin, delineating chromosomal territories, as well as structural partitions analogous to topologically associating domains and active / passive epigenomic compartments. In addition to the overall genome architecture shown by effective interactions, the affinity between partitions of different chromosomes was analyzed as an indicator of the degree of association between partitions in functionally relevant genomic interactions. The overall static picture of whole-genome interactions obtained with the method presented in this work provides a foundation for chromatin structural reconstruction, for the modelling of chromatin dynamics, and for exploring the regulation of genome function. The algorithms used in this study are implemented in a freely available Python package ChromaWalker (https://bitbucket.org/ZhenWahTan/chromawalker).
Subject(s)
Chromatin/genetics , Models, Genetic , Algorithms , CCCTC-Binding Factor/metabolism , Cell Cycle Proteins/metabolism , Cell Line , Chromatin/metabolism , Chromatin Assembly and Disassembly , Chromosomal Proteins, Non-Histone/metabolism , Chromosomes, Human, Pair 17/genetics , Chromosomes, Human, Pair 17/metabolism , Computational Biology , DNA/genetics , DNA/metabolism , DNA-Directed RNA Polymerases/metabolism , Epigenesis, Genetic , Gene Expression Regulation , Gene Regulatory Networks , Genome, Human , Histone Code/genetics , Humans , Markov Chains , CohesinsABSTRACT
The Oct4 gene is a master regulator of the pluripotent properties of embryonic stem cells (ESCs). Recently, Oct4 loci were shown to frequently localize in close proximity to one another during the early stage of cellular differentiation, implicating this event as an important prerequisite step for ESCs to exert their full differentiation potential. Although the differentiation capacity of embryonal carcinoma cells (ECCs), such as F9 and P19 ECC lines, is severely restricted compared with ESCs, ECCs bear a highly similar expression profile to that of ESCs including expression of Oct4 and other pluripotency marker genes. Therefore, we examined whether allelic pairing of Oct4 loci also occurs during differentiation of F9 and P19 ECCs. Our data clearly demonstrate that this event is only observed within ESCs, but not ECCs, subjected to induction of differentiation, indicating transient allelic pairing of Oct4 loci as a specific feature of pluripotent ESCs. Moreover, our data revealed that this pairing did not occur broadly across chromosome 17, which carries the Oct4 gene, but occurred locally between Oct4 loci, suggesting that Oct4 loci somehow exert a driving force for their allelic pairing.
Subject(s)
Cell Differentiation , Chromosomes, Human, Pair 17 , Genetic Loci , Human Embryonic Stem Cells/metabolism , Octamer Transcription Factor-3 , Alleles , Cell Line , Chromosomes, Human, Pair 17/genetics , Chromosomes, Human, Pair 17/metabolism , Human Embryonic Stem Cells/cytology , Humans , Octamer Transcription Factor-3/biosynthesis , Octamer Transcription Factor-3/geneticsABSTRACT
Type 2 diabetes (T2D) affects Latinos at twice the rate seen in populations of European descent. We recently identified a risk haplotype spanning SLC16A11 that explains â¼20% of the increased T2D prevalence in Mexico. Here, through genetic fine-mapping, we define a set of tightly linked variants likely to contain the causal allele(s). We show that variants on the T2D-associated haplotype have two distinct effects: (1) decreasing SLC16A11 expression in liver and (2) disrupting a key interaction with basigin, thereby reducing cell-surface localization. Both independent mechanisms reduce SLC16A11 function and suggest SLC16A11 is the causal gene at this locus. To gain insight into how SLC16A11 disruption impacts T2D risk, we demonstrate that SLC16A11 is a proton-coupled monocarboxylate transporter and that genetic perturbation of SLC16A11 induces changes in fatty acid and lipid metabolism that are associated with increased T2D risk. Our findings suggest that increasing SLC16A11 function could be therapeutically beneficial for T2D. VIDEO ABSTRACT.
Subject(s)
Diabetes Mellitus, Type 2/metabolism , Monocarboxylic Acid Transporters/genetics , Monocarboxylic Acid Transporters/metabolism , Basigin/metabolism , Cell Membrane/metabolism , Chromosomes, Human, Pair 17/metabolism , Gene Knockdown Techniques , Haplotypes , Hepatocytes/metabolism , Heterozygote , Histone Code , Humans , Liver/metabolism , Models, Molecular , Monocarboxylic Acid Transporters/chemistrySubject(s)
Chromosomes, Human, Pair 17/genetics , Chromosomes, Human, Pair 3/genetics , Fibronectins/genetics , Leukemia, Promyelocytic, Acute/genetics , Oncogene Proteins, Fusion/genetics , Retinoic Acid Receptor alpha/genetics , Translocation, Genetic , Adult , Chromosomes, Human, Pair 17/metabolism , Chromosomes, Human, Pair 3/metabolism , Fibronectins/metabolism , Humans , Leukemia, Promyelocytic, Acute/metabolism , Male , Oncogene Proteins, Fusion/metabolism , Retinoic Acid Receptor alpha/metabolismABSTRACT
Human herpesvirus 6B (HHV-6B) is a neurotropic betaherpesvirus that achieves latency by integrating its genome into host cell chromosomes. Several viruses can induce epigenetic modifications in their host cells, but no study has investigated the epigenetic modifications induced by HHV-6B. This study analyzed methylation with an Illumina 450K array, comparing HHV-6B-infected and uninfected Molt-3 T cells 3 days postinfection. Bisulfite pyrosequencing was used to validate the Illumina results and to investigate methylation over time in vitro Expression of genes was investigated using quantitative PCR (qPCR), and virus integration was investigated with PCR. A total of 406 CpG sites showed a significant HHV-6B-induced change in methylation in vitro Remarkably, 86% (351/406) of these CpGs were located <1 Mb from chromosomal ends and were all hypomethylated in virus-infected cells. This was most evident at chromosome 17p13.3, where HHV-6B had induced CpG hypomethylation after 2 days of infection, possibly through TET2, which was found to be upregulated by the virus. In addition, virus-induced cytosine hydroxymethylation was observed. Genes located in the hypomethylated region at 17p13.3 showed significantly upregulated expression in HHV-6B-infected cells. A temporal experiment revealed HHV-6B integration in Molt-3 cell DNA 3 days after infection. The telomere at 17p has repeatedly been described as an integration site for HHV-6B, and we show for the first time that HHV-6B induces hypomethylation in this region during acute infection, which may play a role in the integration process, possibly by making the DNA more accessible.IMPORTANCE The ability to establish latency in the host is a hallmark of herpesviruses, but the mechanisms differ. Human herpesvirus 6B (HHV-6B) is known to establish latency through integration of its genome into the telomeric regions of host cells, with the ability to reactivate. Our study is the first to show that HHV-6B specifically induces hypomethylated regions close to the telomeres and that integrating viruses may use the host methylation machinery to facilitate their integration process. The results from this study contribute to knowledge of HHV-6B biology and virus-host interaction. This in turn will lead to further progress in our understanding of the underlying mechanisms by which HHV-6B contributes to pathological processes and may have important implications in both disease prevention and treatment.