48,731 results on '"Translocation, Genetic"'
Search Results
2. FISH联合染色体核型分析明确复发性流产家系遗传病因-例.
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庄建龙, 江商颖, 曾书红, and 陈新英
- Abstract
The etiology of spontaneous abortion is complex, including embryonic factors, maternal factors, environmental factors and abnormal immune function. Approximately 50% ~60% abortions are related to fetal chromosomal abnormalities. We reported a case of twice spontaneous abortion. The couple were subject to both chromosome karyotype and fluorescence in situ hybridization (FISH) analysis. None of obvious abnormality was observed in the wife, while chromosome karyotype result showed 46,XY,t(1;11)(p36.2;q24) in the husband. The balanced translocation of t(1;11) carried by the husband may be the reason for recurrent spontaneous abortion in this family. The case indicated the application value of FISH technology in the verification of suspect subtelomeric rearrangements. [ABSTRACT FROM AUTHOR]
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- 2024
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3. 低级别子宫内膜间质肉瘤.
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季安璇, 张群, 王晴, and 赵淑华
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Low-grade endometrial stromal sarcoma (LG-ESS) is a rare type of malignant tumor of mesenchymal origin, which is also known as the most common subtype of endometrial stromal sarcoma. As a genetically heterogeneous disease, LGESS has many characteristic chromosomal translocations. Abnormal fusion proteins expressed by fusion genes are an important driving factor for the development of LG-ESS and also provide potential therapeutic targets for LG-ESS. LG-ESS is a low-grade malignant tumor characterized by slow growth and late recurrence, with pelvic radiation and long-term use of tamoxifen or estrogen as important risk factors. Due to the atypial of clinical manifestations, there is still a lack of effective preoperative diagnosis. Morphology and combined application of immunohistochemical antibodies can improve the detection rate, but their value is limited. Therefore, its diagnosis and treatment remains a great challenge for clinicians. This article reviews the molecular mechanisms, clinical manifestations, pathological diagnosis, treatment and prognosis of LG-ESS. [ABSTRACT FROM AUTHOR]
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- 2022
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4. Rearrangements involving 11q23.3/KMT2A in adult AML: mutational landscape and prognostic implications - a HARMONY study.
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Hernández-Sánchez A, González T, Sobas M, Sträng E, Castellani G, Abáigar M, Valk PJM, Villaverde Ramiro Á, Benner A, Metzeler KH, Azibeiro R, Tettero JM, Martínez-López J, Pratcorona M, Martínez Elicegui J, Mills KI, Thiede C, Sanz G, Döhner K, Heuser M, Haferlach T, Turki AT, Reinhardt D, Schulze-Rath R, Barbus M, Hernández-Rivas JM, Huntly B, Ossenkoppele G, Döhner H, and Bullinger L
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- Humans, Middle Aged, Prognosis, Adult, Female, Male, Aged, Young Adult, Translocation, Genetic, Gene Rearrangement, Adolescent, Aged, 80 and over, Survival Rate, High-Throughput Nucleotide Sequencing, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute mortality, Leukemia, Myeloid, Acute therapy, Myeloid-Lymphoid Leukemia Protein genetics, Histone-Lysine N-Methyltransferase genetics, Mutation, Chromosomes, Human, Pair 11 genetics
- Abstract
Balanced rearrangements involving the KMT2A gene (KMT2Ar) are recurrent genetic abnormalities in acute myeloid leukemia (AML), but there is lack of consensus regarding the prognostic impact of different fusion partners. Moreover, prognostic implications of gene mutations co-occurring with KMT2Ar are not established. From the HARMONY AML database 205 KMT2Ar adult patients were selected, 185 of whom had mutational information by a panel-based next-generation sequencing analysis. Overall survival (OS) was similar across the different translocations, including t(9;11)(p21.3;q23.3)/KMT2A::MLLT3 (p = 0.756). However, independent prognostic factors for OS in intensively treated patients were age >60 years (HR 2.1, p = 0.001), secondary AML (HR 2.2, p = 0.043), DNMT3A-mut (HR 2.1, p = 0.047) and KRAS-mut (HR 2.0, p = 0.005). In the subset of patients with de novo AML < 60 years, KRAS and TP53 were the prognostically most relevant mutated genes, as patients with a mutation of any of those two genes had a lower complete remission rate (50% vs 86%, p < 0.001) and inferior OS (median 7 vs 30 months, p < 0.001). Allogeneic hematopoietic stem cell transplantation in first complete remission was able to improve OS (p = 0.003). Our study highlights the importance of the mutational patterns in adult KMT2Ar AML and provides new insights into more accurate prognostic stratification of these patients., (© 2024. The Author(s).)
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- 2024
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5. Outcomes of venetoclax-based therapy in patients with t(11;14) light chain amyloidosis after failure of daratumumab-based therapy.
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Dima D, Hughes M, Orland M, Ullah F, Goel U, Anwer F, Raza S, Mazzoni S, Bhutani D, Williams L, Lentzsch S, Samaras C, Valent J, Chakraborty R, and Khouri J
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- Humans, Male, Female, Middle Aged, Aged, Retrospective Studies, Chromosomes, Human, Pair 11 genetics, Adult, Aged, 80 and over, Translocation, Genetic, Treatment Outcome, Antineoplastic Agents therapeutic use, Bridged Bicyclo Compounds, Heterocyclic therapeutic use, Bridged Bicyclo Compounds, Heterocyclic administration & dosage, Sulfonamides therapeutic use, Sulfonamides administration & dosage, Antibodies, Monoclonal therapeutic use, Antibodies, Monoclonal administration & dosage, Immunoglobulin Light-chain Amyloidosis drug therapy, Immunoglobulin Light-chain Amyloidosis genetics, Immunoglobulin Light-chain Amyloidosis mortality, Immunoglobulin Light-chain Amyloidosis pathology, Chromosomes, Human, Pair 14 genetics
- Abstract
Background: Daratumumab's incorporation in the upfront treatment of light chain (AL) amyloidosis has led to daratumumab (dara) refractoriness early in disease course. Patients who experience relapse or have suboptimal response to dara-based-therapy, have limited options., Objective: This study aimed to evaluate the outcomes of venetoclax-based therapy in t(11;14) positive AL patients who previously failed dara., Methods: Thirty-one patients with AL were included in this bi-institutional retrospective analysis., Results: Dara failure was due to inadequate response in 20 (65%) patients, haematologic relapse in 7 (22%), and both haematologic plus organ relapse in 4 (13%). Overall haematologic response rate to venetoclax-based therapy was 97%, with ≥ VGPR being 91%. Of the 19 evaluable patients with cardiac involvement, 14 (74%) achieved organ response. Of the 13 evaluable patients with renal involvement, 6 (46%) achieved organ response. With a median follow-up of 22 months, median time-to-next-treatment (TTNT) and overall survival (OS) were not reached. The 12- and 24-month TTNT rates were 74% and 56%, respectively. At data-cut-off, four patients had died, all from AL-related organ complications. The 12- and 24-month OS rates were 89% and 85%, respectively. Grade ≥3 adverse events occurred in 26% of patients, with 6% due to infections., Conclusion: These findings are encouraging for the use of venetoclax as salvage therapy post-dara failure.
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- 2024
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6. Myeloid neoplasm with <10% blasts and t(3;5)(q25.1;q34)/NPM::MLF1: A classification dilemma.
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Sameeta F, Fang H, Wang W, Tang Z, Wang SA, Toruner GA, Parisi X, Khoury JD, Issa G, Garcia-Manero G, Medeiros LJ, Tang G, and Loghavi S
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- Humans, Chromosomes, Human, Pair 5 genetics, Chromosomes, Human, Pair 3 genetics, Male, Oncogene Proteins, Fusion genetics, Myeloproliferative Disorders genetics, Myeloproliferative Disorders classification, Myeloproliferative Disorders diagnosis, Myeloproliferative Disorders pathology, Female, Middle Aged, Translocation, Genetic
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- 2024
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7. Pediatric acute myeloid leukemia with t(8;21) and KIT mutation treatment with avapritinib post-stem cell transplantation: a report of four cases.
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Wang Q, Hu Y, Gao L, Zhang S, Lu J, Li B, Li J, Yao Y, Cheng S, Xiao P, and Hu S
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- Humans, Male, Female, Child, Child, Preschool, Pyrazines therapeutic use, Pyrazines adverse effects, Adolescent, Pyrazoles therapeutic use, Pyrazoles adverse effects, Oncogene Proteins, Fusion genetics, Retrospective Studies, Pyrroles therapeutic use, Pyrroles adverse effects, Core Binding Factor Alpha 2 Subunit genetics, Triazines, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute therapy, Leukemia, Myeloid, Acute drug therapy, Proto-Oncogene Proteins c-kit genetics, Translocation, Genetic, Hematopoietic Stem Cell Transplantation, Mutation, Chromosomes, Human, Pair 21 genetics, Chromosomes, Human, Pair 8 genetics
- Abstract
Acute myeloid leukemia (AML) with t(8;21) (q22;q22), which forms RUNX1::RUNX1T1 fusion gene, is classified as a favorable-risk group. However, the presence of mutations in KIT exon 17 results in an adverse prognosis in this group. Avapritinib, a novel tyrosine kinase inhibitor, was designed to target KIT mutation. We report a retrospective study of four pediatric patients with AML with t(8:21) and KIT exon 17 mutation who were treated with avapritinib, three of them failed to demethylate drugs and donor lymphocyte infusion targeting RUNX1::RUNX1T1-positivity after allogeneic hematopoietic stem cell transplantation (allo-HSCT). So far, all patients with RUNX1::RUNX1T1 positivity had turned negative after 1, 9, 7, 2 months of avapritinib treatment. The common adverse effect of avapritinib is neutropenia, which is well-tolerated. This case series indicates that avapritinib may be effective and safe for preemptive treatment of children with AML with t(8;21) and KIT mutation after allo-HSCT, providing a treatment option for preventing relapse after allo-HSCT., (© 2024. The Author(s).)
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- 2024
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8. Molecular landscape of mature B-cell lymphoproliferative disorders with BCL3-translocation: A Groupe Francophone de Cytogénétique Hématologique (GFCH)/French Innovative Leukemia Organization (FILO) study.
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Véronèse L, Bensaber H, Dannus LT, Giannone G, Choiset C, Grimpret C, Abermil N, Balducci E, Bidet A, Chapiro E, Couronné L, Daudignon A, Douet-Gilbert N, Eclache V, Gaillard B, Gaillard JB, Hsoumi F, Lefebvre C, Nadal N, Mozziconacci MJ, Penther D, Ribourtout B, Richebourg S, Rigollet L, Terre C, Soler G, Tournilhac O, Guièze R, Nguyen-Khac F, and Tchirkov A
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- Humans, Male, Female, Middle Aged, Lymphoproliferative Disorders genetics, Lymphoproliferative Disorders diagnosis, Aged, B-Lymphocytes metabolism, B-Lymphocytes pathology, Adult, France, B-Cell Lymphoma 3 Protein, Translocation, Genetic
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- 2024
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9. Chronic Myeloid Leukemia with a Rare Philadelphia Chromosome Variant Involving Chromosome 16.
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Bahashwan SM
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- Humans, Female, Adult, Imatinib Mesylate therapeutic use, Fusion Proteins, bcr-abl genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Philadelphia Chromosome, Translocation, Genetic, Chromosomes, Human, Pair 16 genetics
- Abstract
BACKGROUND Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by the presence of the Philadelphia (Ph) chromosome, which results from the fusion of the translocation of the ABL1 gene from chromosome 9 to the BCR gene located in chromosome 22, forming the BCR-ABL gene on chromosome number 22, which accounts for approximately 95% of CML cases. Complex translocation involving other chromosomes can occur. CASE REPORT We present a rare case of CML with a variant Ph chromosome, in which chromosome 16 was involved with the usual translocation. A 34-year-old woman presented with a history of left upper quadrant pain and excessive sweating, with no hepatosplenomegaly on examination. She was found to have leukocytosis, with elevated neutrophils (34 000/mm³), basophils (1460/mm³), and eosinophils (2650/mm³). Karyotyping showed a translocation (16;22) (q24,q11.2), and FISH analysis showed BCR-ABL fusion as a result of (9,22) translocation, with a third chromosome (chromosome 16) involved and fused with chromosome 22, with a different breakpoint, which has never been reported in the literature, affecting the long arm of chromosome 16. The patient was treated with a first-generation tyrosine kinase inhibitor (imatinib) and achieved a deep molecular remission. The repeated FISH analysis confirmed the disappearance of both translocations (9,22) and (16,22). CONCLUSIONS The impact of the additional chromosomal aberration in CML is widely heterogeneous, and the outcome is dependent on multiple factors. Larger studies are needed to clarify the outcome in CML with variant Ph chromosomes, as most of the available data come from reported cases.
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- 2024
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10. Clonal evolution of the 3D chromatin landscape in patients with relapsed pediatric B-cell acute lymphoblastic leukemia.
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Narang S, Ghebrechristos Y, Evensen NA, Murrell N, Jasinski S, Ostrow TH, Teachey DT, Raetz EA, Lionnet T, Witkowski M, Aifantis I, Tsirigos A, and Carroll WL
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- Humans, Child, Chromatin Assembly and Disassembly genetics, Child, Preschool, Male, Translocation, Genetic, Female, Recurrence, Adolescent, Chromatin metabolism, Chromatin genetics, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma pathology, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma metabolism, Clonal Evolution genetics
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Relapsed pediatric B-cell acute lymphoblastic leukemia (B-ALL) remains one of the leading causes of cancer mortality in children. We performed Hi-C, ATAC-seq, and RNA-seq on 12 matched diagnosis/relapse pediatric leukemia specimens to uncover dynamic structural variants (SVs) and 3D chromatin rewiring that may contribute to relapse. While translocations are assumed to occur early in leukemogenesis and be maintained throughout progression, we discovered novel, dynamic translocations and confirmed several fusion transcripts, suggesting functional and therapeutic relevance. Genome-wide chromatin remodeling was observed at all organizational levels: A/B compartments, TAD interactivity, and chromatin loops, including some loci shared by 25% of patients. Shared changes were found to drive the expression of genes/pathways previously implicated in resistance as well as novel therapeutic candidates, two of which (ATXN1 and MN1) we functionally validated. Overall, these results demonstrate chromatin reorganization under the selective pressure of therapy and offer the potential for discovery of novel therapeutic interventions., (© 2024. The Author(s).)
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- 2024
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11. Identification of a Novel MAPK1::BCR Fusion Gene/t(9;22) (q34;q11) in a Case of Acute Promyelocytic Leukemia
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Wang Q, Zeng LJ, Wang M, Weng JY, and Pan JL
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- Humans, Male, Proto-Oncogene Proteins c-bcr genetics, Female, Adult, Mitogen-Activated Protein Kinase 1, Leukemia, Promyelocytic, Acute genetics, Leukemia, Promyelocytic, Acute diagnosis, Translocation, Genetic, Oncogene Proteins, Fusion genetics, Chromosomes, Human, Pair 22 genetics, Chromosomes, Human, Pair 9 genetics
- Abstract
Competing Interests: Conflict of Interest: No conflict of interest was declared by the authors.
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- 2024
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12. KMT2A Rearrangements in Leukemias: Molecular Aspects and Therapeutic Perspectives.
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Guarnera L, D'Addona M, Bravo-Perez C, and Visconte V
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- Humans, Hematopoietic Stem Cell Transplantation, Translocation, Genetic, Myeloid-Lymphoid Leukemia Protein genetics, Histone-Lysine N-Methyltransferase genetics, Gene Rearrangement, Leukemia genetics, Leukemia therapy
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KMT2A (alias: mixed-lineage leukemia [ MLL ]) gene mapping on chromosome 11q23 encodes the lysine-specific histone N-methyltransferase 2A and promotes transcription by inducing an open chromatin conformation. Numerous genomic breakpoints within the KMT2A gene have been reported in young children and adults with hematologic disorders and are present in up to 10% of acute leukemias. These rearrangements describe distinct features and worse prognosis depending on the fusion partner, characterized by chemotherapy resistance and high rates of relapse, with a progression-free survival of 30-40% and overall survival below 25%. Less intensive regimens are used in pediatric patients, while new combination therapies and targeted immunotherapeutic agents are being explored in adults. Beneficial therapeutic effects, and even cure, can be reached with hematopoietic stem cell transplantation, mainly in young children with dismal molecular lesions; however, delayed related toxicities represent a concern. Herein, we summarize the translocation partner genes and partial tandem duplications of the KMT2A gene, their molecular impact, clinical aspects, and novel targeted therapies.
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- 2024
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13. Transformation into acute myeloid leukemia with t(8;21)(q22;q22.1); RUNX1::RUNX1T1 from JAK2-mutated essential thrombocythemia: a case report.
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Asou C, Sakamoto T, Suzuki K, Okuda I, Osaki A, Abe R, Ito Y, Kakegawa E, Miyakawa Y, Terui Y, and Nakamura Y
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- Humans, Female, Aged, RUNX1 Translocation Partner 1 Protein genetics, Chromosomes, Human, Pair 8 genetics, Chromosomes, Human, Pair 21 genetics, Mutation, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute drug therapy, Janus Kinase 2 genetics, Core Binding Factor Alpha 2 Subunit genetics, Thrombocythemia, Essential genetics, Thrombocythemia, Essential drug therapy, Translocation, Genetic
- Abstract
Background: Blast transformation is a rare but well-recognized event in Philadelphia-negative myeloproliferative neoplasms associated with a poor prognosis. Secondary acute myeloid leukemias evolving from myeloproliferative neoplasms are characterized by a unique set of cytogenetic and molecular features distinct from de novo disease. t(8;21) (q22;q22.1); RUNX1::RUNX1T1, one of the most frequent cytogenetic abnormalities in de novo acute myeloid leukemia, is rarely observed in post-myeloproliferative neoplasm acute myeloid leukemia. Here we report a case of secondary acute myeloid leukemia with t(8;21) evolving from JAK2-mutated essential thrombocythemia., Case Presentation: The patient was a 74-year-old Japanese woman who was referred because of thrombocytosis (platelets 1046 × 10
9 /L). Bone marrow was hypercellular with increase of megakaryocytes. Chromosomal analysis presented normal karyotype and genetic test revealed JAK2 V617F mutation. She was diagnosed with essential thrombocythemia. Thrombocytosis had been well controlled by oral administration of hydroxyurea; 2 years after the initial diagnosis with ET, she presented with leukocytosis (white blood cells 14.0 × 109 /L with 82% of blasts), anemia (hemoglobin 91 g/L), and thrombocytopenia (platelets 24 × 109 /L). Bone marrow was hypercellular and filled with 80% of myeloperoxidase-positive blasts bearing Auer rods. Chromosomal analysis revealed t(8;21) (q22;q22.1) and flow cytometry presented positivity of CD 13, 19, 34, and 56. Molecular analysis showed the coexistence of RUNX1::RUNX1T1 chimeric transcript and heterozygous JAK2 V617F mutation in leukemic blasts. She was diagnosed with secondary acute myeloid leukemia with t(8;21)(q22;q22.1); RUNX1::RUNX1T1 evolving from essential thrombocythemia. She was treated with combination chemotherapy with venetoclax and azacytidine. After the first cycle of the therapy, blasts disappeared from peripheral blood and decreased to 1.4% in bone marrow. After the chemotherapy, RUNX1::RUNX1T1 chimeric transcript disappeared, whereas mutation of JAK2 V617F was still present in peripheral leukocytes., Conclusions: To our best knowledge, the present case is the first one with JAK2 mutation preceding the acquisition of t(8;21). Our result suggests that t(8;21); RUNX1::RUNX1T1 can be generated as a late event in the progression of JAK2-mutated myeloproliferative neoplasms. The case presented typical morphological and immunophenotypic features associated with t(8;21) acute myeloid leukemia., (© 2024. The Author(s).)- Published
- 2024
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14. The biological and clinical impact of deletions before and after large chromosomal gains in multiple myeloma.
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Cirrincione AM, Poos AM, Ziccheddu B, Kaddoura M, Bärtsch MA, Maclachlan K, Chojnacka M, Diamond B, John L, Reichert P, Huhn S, Blaney P, Gagler D, Rippe K, Zhang Y, Dogan A, Lesokhin AM, Davies F, Goldschmidt H, Fenk R, Weisel KC, Mai EK, Korde N, Morgan GJ, Usmani S, Landgren O, Raab MS, Weinhold N, and Maura F
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- Humans, Translocation, Genetic, Immunoglobulin Heavy Chains genetics, Chromosome Aberrations, Gene Deletion, Male, Female, Genes, Tumor Suppressor, Multiple Myeloma genetics
- Abstract
Abstract: Acquisition of a hyperdiploid (HY) karyotype or immunoglobulin heavy chain (IgH) translocations are considered key initiating events in multiple myeloma (MM). To explore if other genomic events can precede these events, we analyzed whole-genome sequencing data from 1173 MM samples. By integrating molecular time and structural variants within early chromosomal duplications, we indeed identified pregain deletions in 9.4% of patients with an HY karyotype without IgH translocations, challenging acquisition of an HY karyotype as the earliest somatic event. Remarkably, these deletions affected tumor suppressor genes (TSGs) and/or oncogenes in 2.4% of patients with an HY karyotype without IgH translocations, supporting their role in MM pathogenesis. Furthermore, our study points to postgain deletions as novel driver mechanisms in MM. Using multiomics approaches to investigate their biologic impact, we found associations with poor clinical outcome in newly diagnosed patients and profound effects on both the oncogene and TSG activity despite the diploid gene status. Overall, this study provides novel insights into the temporal dynamics of genomic alterations in MM., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)
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- 2024
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15. Clinical features and prognosis of patients with myeloid neoplasms harboring t(7;11)(p15;p15) translocation: a single-center retrospective study.
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Liu L, Zhao S, Wang L, Xu H, Chen Z, Tu J, Huang J, Jin J, and Tong H
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- Humans, Female, Male, Retrospective Studies, Adult, Middle Aged, Prognosis, Young Adult, Aged, Adolescent, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute mortality, Leukemia, Myeloid, Acute therapy, Leukemia, Myeloid, Acute pathology, Chromosomes, Human, Pair 7 genetics, Myelodysplastic Syndromes genetics, Myelodysplastic Syndromes mortality, Myelodysplastic Syndromes therapy, Translocation, Genetic, Chromosomes, Human, Pair 11 genetics
- Abstract
Background: For myeloid neoplasms with t(7;11)(p15;p15) translocation, the prognosis is quite dismal. Because these tumors are rare, most occurrences are reported as single cases. Clinical results and optimal treatment approaches remain elusive. This study endeavors to elucidate the clinical implications and prognosis of this cytogenetic aberration., Methods: This study retrospectively analyzed 23 cases of myeloid neoplasm with t(7;11)(p15;p15). Clinicopathological characteristics, genetic alterations, and outcomes were evaluated, and the Kaplan-Meier method was employed to construct survival curves., Results: Of these, nine cases were newly diagnosed acute myeloid leukemia (ND AML), seven presented with relapsed refractory AML (R/R AML), four had myelodysplastic syndrome (MDS), two had secondary AML, and one exhibited a mixed germinoma associated with MDS. Patients with t(7;11)(p15;p15) in AML were primarily younger females who preferred subtype M2. Interestingly, these patients had decreased hemoglobin and red blood cell counts, along with markedly elevated levels of lactic dehydrogenase and interleukin-6, and exhibited the expression of CD117. R/R AML patients exhibited a higher likelihood of additional chromosome abnormalities (ACAs) besides t(7;11). WT1 and FLT3-ITD were the most commonly found mutated genes, and 10 of those instances showed evidence of the NUP98::HOXA9 fusion gene. The composite complete remission rate was 66.7% (12/18), while the cumulative graft survival rate was 100% (4/4). However, the survival outcomes were dismal. Interestingly, the median overall survival for R/R AML patients was 4.0 months (95% CI: 1.7-6.4). Additionally, the type of AML diagnosis or the presence of ACAs or molecular prognostic stratification did not significantly influence clinical outcomes (p = 0.066, p = 0.585, p = 0.570, respectively)., Conclusion: Myeloid leukemia with t(7;11) exhibits unique clinical features, cytogenetic properties, and molecular genetic characteristics. These survival outcomes were dismal. R/R AML patients have a limited lifespan. For myeloid patients with t(7;11), targeted therapy or transplantation may be an effective course of treatment., (© 2024. The Author(s).)
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- 2024
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16. ATM and 53BP1 regulate alternative end joining-mediated V(D)J recombination.
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Wang J, Sadeghi CA, Le LV, Le Bouteiller M, and Frock RL
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- Animals, Humans, DNA Breaks, Double-Stranded, Mice, DNA Damage, Translocation, Genetic, Tumor Suppressor p53-Binding Protein 1 metabolism, Tumor Suppressor p53-Binding Protein 1 genetics, Ataxia Telangiectasia Mutated Proteins metabolism, Ataxia Telangiectasia Mutated Proteins genetics, V(D)J Recombination, DNA End-Joining Repair
- Abstract
G
0 -G1 phase alternative end joining (A-EJ) is a recently defined mutagenic pathway characterized by resected deletion and translocation joints that are predominantly direct and are distinguished from A-EJ in cycling cells that rely much more on microhomology-mediated end joining (MMEJ). Using chemical and genetic approaches, we systematically evaluate potential A-EJ factors and DNA damage response (DDR) genes to support this mechanism by mapping the repair fates of RAG1/2-initiated double-strand breaks in the context of Igκ locus V-J recombination and chromosome translocation. Our findings highlight a polymerase theta-independent Parp1-XRCC1/LigIII axis as central A-EJ components, supported by 53BP1 in the context of an Ataxia-telangiectasia mutated (ATM)-activated DDR. Mechanistically, we demonstrate varied changes in short-range resection, MMEJ, and translocation, imposed by compromising specific DDR activities, which include polymerase alpha, Ataxia-telangiectasia and Rad3-related (ATR), DNA2, and Mre11. This study advances our understanding of DNA damage repair within the 53BP1 regulatory domain and the RAG1/2 postcleavage complex.- Published
- 2024
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17. A complex t(15;22;17)(q22;q11.2;q21) variant of APL.
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Ak B, Güngör Ö, Karaca E, Durmaz B, Bozer DS, Töbü M, and Akın H
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- Humans, Male, Aged, Tretinoin therapeutic use, Chromosomes, Human, Pair 15 genetics, Chromosomes, Human, Pair 22 genetics, In Situ Hybridization, Fluorescence, Leukemia, Promyelocytic, Acute genetics, Leukemia, Promyelocytic, Acute drug therapy, Translocation, Genetic, Chromosomes, Human, Pair 17 genetics
- Abstract
The present study described an extremely rare case of acute promyelocytic leukemia (APL) characterized by a complex three‑way (15;22;17)(q22;q11.2;q21) translocation. Acute promyelocytic leukemia (APL) is a specific subtype of acute myeloid leukemia with distinctive clinical and therapeutic characteristics. Besides being characterized by the t(15;17)(q22;q12) translocation, this subtype is also notable for its response to all-trans-retinoic acid (ATRA) treatment. APL is highly responsive to a combination of ATRA and chemotherapeutic agents, achieving over 90 % complete remission rates and over 80 % long-term remission rates. In this case, a 79-year-old male patient presented with complaints of weakness, fatigue, and petechial rash, with no other significant medical history except for diabetes mellitus and hypertension. Conventional cytogenetic methods, dual-color dual-fusion, and dual-color break-apart fluorescent in situ hybridization techniques together identified the t(15;22;17) translocation. RT-PCR analysis was performed for expression of PML/RARA fusion transcripts. The patient, diagnosed with APL, exhibited a complete response to all-trans retinoic acid (ATRA) and idarubicin treatment. In this paper, we present the second documented case of t(15;22;17) and explore the remarkable remission observed following treatment with All-Trans Retinoic Acid (ATRA)., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)
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- 2024
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18. MYC translocation architecture in B-NHL.
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Küppers R
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- Humans, Proto-Oncogene Proteins c-myc genetics, Proto-Oncogene Proteins c-myc metabolism, Lymphoma, B-Cell genetics, Lymphoma, B-Cell pathology, Male, Female, Translocation, Genetic
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- 2024
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19. Comprehensive molecular characterization of TFE3-rearranged renal cell carcinoma.
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Lee CR, Suh J, Jang D, Jin BY, Cho J, Lee M, Sim H, Kang M, Lee J, Park JH, Lee KH, Hwang GS, Moon KC, Song C, Ku JH, Kwak C, Kim HH, Cho SY, Choi M, and Jeong CW
- Subjects
- Humans, Female, Male, Middle Aged, Aged, Adult, Gene Rearrangement, Gene Expression Regulation, Neoplastic, Cell Line, Tumor, Gene Expression Profiling, Translocation, Genetic, Transcriptome, Polymorphism, Single Nucleotide, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Carcinoma, Renal Cell genetics, Carcinoma, Renal Cell pathology, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors genetics, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors metabolism, Kidney Neoplasms genetics, Kidney Neoplasms pathology, Exome Sequencing
- Abstract
TFE3-rearranged renal cell cancer (tRCC) is a rare form of RCC that involves chromosomal translocation of the Xp11.2 TFE3 gene. Despite its early onset and poor prognosis, the molecular mechanisms of the pathogenesis of tRCC remain elusive. This study aimed to identify novel therapeutic targets for patients with primary and recurrent tRCC. We collected 19 TFE3-positive RCC tissues that were diagnosed by immunohistochemistry and subjected them to genetic characterization to examine their genomic and transcriptomic features. Tumor-specific signatures were extracted using whole exome sequencing (WES) and RNA sequencing (RNA-seq) data, and the functional consequences were analyzed in a cell line with TFE3 translocation. Both a low burden of somatic single nucleotide variants (SNVs) and a positive correlation between the number of somatic variants and age of onset were observed. Transcriptome analysis revealed that four samples (21.1%) lacked the expected fusion event and clustered with the genomic profiles of clear cell RCC (ccRCC) tissues. The fusion event also demonstrated an enrichment of upregulated genes associated with mitochondrial respiration compared with ccRCC expression profiles. Comparison of the RNA expression profile with the TFE3 ChIP-seq pattern data indicated that PPARGC1A is a metabolic regulator of the oncogenic process. Cell proliferation was reduced when PPARGC1A and its related metabolic pathways were repressed by its inhibitor SR-18292. In conclusion, we demonstrate that PPARGC1A-mediated mitochondrial respiration can be considered a potential therapeutic target in tRCC. This study identifies an uncharacterized genetic profile of an RCC subtype with unique clinical features and provides therapeutic options specific to tRCC., (© 2024. The Author(s).)
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- 2024
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20. Combination of menin and kinase inhibitors as an effective treatment for leukemia with NUP98 translocations.
- Author
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Miao H, Chen D, Ropa J, Purohit T, Kim E, Sulis ML, Ferrando A, Cierpicki T, and Grembecka J
- Subjects
- Humans, Animals, Mice, Xenograft Model Antitumor Assays, Piperazines pharmacology, Piperazines therapeutic use, Pyridines pharmacology, Pyridines therapeutic use, Cyclin-Dependent Kinase 6 antagonists & inhibitors, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute pathology, Antineoplastic Combined Chemotherapy Protocols pharmacology, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Cell Proliferation drug effects, Drug Synergism, fms-Like Tyrosine Kinase 3 genetics, fms-Like Tyrosine Kinase 3 antagonists & inhibitors, Cell Line, Tumor, Aniline Compounds, Pyrazines, Nuclear Pore Complex Proteins genetics, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors therapeutic use, Proto-Oncogene Proteins genetics, Translocation, Genetic
- Abstract
Chromosomal translocations of the nucleoporin 98 (NUP98) gene are found in acute myeloid leukemia (AML) patients leading to very poor outcomes. The oncogenic activity of NUP98 fusion proteins is dependent on the interaction between Mixed Lineage Leukemia 1 and menin. NUP98-rearranged (NUP98-r) leukemia cells also rely on specific kinases, including CDK6 and/or FLT3, suggesting that simultaneous targeting of these kinases and menin could overcome limited sensitivity to single agents. Here, we found that combinations of menin inhibitor, MI-3454, with kinase inhibitors targeting either CDK6 (Palbociclib) or FLT3 (Gilteritinib) strongly enhance the anti-leukemic effect of menin inhibition in NUP98-r leukemia models. We found strong synergistic effects of both combinations on cell growth, colony formation and differentiation in patient samples with NUP98 translocations. These combinations also markedly augmented anti-leukemic efficacy of menin inhibitor in Patient Derived Xenograft models of NUP98-r leukemia. Despite inhibiting two unrelated kinases, when Palbociclib or Gilteritinib were combined with the menin inhibitor, they affected similar pathways relevant to leukemogenesis, including cell cycle regulation, cell proliferation and differentiation. This study provides strong rationale for clinical translation of the combination of menin and kinase inhibitors as novel treatments for NUP98-r leukemia, supporting the unexplored combinations of epigenetic drugs with kinase inhibitors., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
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- 2024
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21. Patients with Classic Hodgkin Lymphoma and Follicular Lymphoma Compared to Single Malignancy Controls.
- Author
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Cotta CV, Bhavsar S, Robertson S, and Cook JR
- Subjects
- Humans, Middle Aged, Female, Male, Aged, Adult, Neoplasms, Multiple Primary pathology, Neoplasms, Multiple Primary genetics, Neoplasms, Multiple Primary virology, Proto-Oncogene Proteins c-bcl-2 genetics, Neoplasm Grading, Herpesvirus 4, Human genetics, Herpesvirus 4, Human isolation & purification, Translocation, Genetic, Aged, 80 and over, Epstein-Barr Virus Infections complications, Epstein-Barr Virus Infections virology, Epstein-Barr Virus Infections pathology, Biomarkers, Tumor genetics, Biomarkers, Tumor analysis, In Situ Hybridization, Fluorescence, Case-Control Studies, Hodgkin Disease pathology, Hodgkin Disease virology, Hodgkin Disease genetics, Lymphoma, Follicular pathology, Lymphoma, Follicular genetics, Lymphoma, Follicular virology
- Abstract
Classic Hodgkin lymphoma (CHL) can arise in patients with low-grade B-cell lymphoma. The features of CHL arising in follicular lymphoma (FL) and its outcome are still unclear, mainly due to the very few cases reported. This study compares 17 patients with CHL and FL to 2 control groups: 1 of 26 patients with FL and a second of 60 patients older than 40 when diagnosed with CHL. Of the FL and CHL patients, 8 had simultaneous FL and CHL, while 9 had FL first, followed by CHL 4.7 years later on average. The age at the diagnosis of FL was 61 years for patients with synchronous FL and CHL and of 60 years for FL, followed by CHL at 65 years. Patients with FL only were, on average, 59 years old at presentation, while CHL patients were 61. FL was grade 1-2 in 75% of FL and CHL patients and 67% of FL first and CHL second patients, lower proportions than in the FL control group-92%. Epstein-Barr virus (EBV) was detected in a lower fraction (29%) of the FL and CHL group than in CHL-only controls (46%). BCL2 translocations were detected in 4 of the 7 cases with FL, but in positive cases, the rearrangement was also present in the CHL component, indicating a clonal relationship between FL and CHL. Patients with FL and CHL treated for CHL had an initial outcome more similar to FL than to CHL controls., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)
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- 2024
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22. Backtracking NOM1::ETV6 fusion to neonatal pathogenesis of t(7;12) (q36;p13) infant AML.
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Bousquets-Muñoz P, Molina O, Varela I, Álvarez-Eguiluz Á, Fernández-Mateos J, Gómez A, Sánchez EG, Balbín M, Ruano D, Ramírez-Orellana M, Puente XS, Menéndez P, and Velasco-Hernandez T
- Subjects
- Humans, Chromosomes, Human, Pair 7 genetics, Infant, Newborn, Infant, Transcription Factors genetics, Male, Female, MDS1 and EVI1 Complex Locus Protein, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute pathology, Translocation, Genetic, Oncogene Proteins, Fusion genetics, ETS Translocation Variant 6 Protein, Repressor Proteins genetics, Chromosomes, Human, Pair 12 genetics, Proto-Oncogene Proteins c-ets genetics
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- 2024
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23. ETV6::ACSL6 translocation-driven super-enhancer activation leads to eosinophilia in acute lymphoblastic leukemia through IL-3 overexpression.
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Xu W, Tian F, Tai X, Song G, Liu Y, Fan L, Weng X, Yang E, Wang M, Bornhäuser M, Zhang C, Lock RB, Wong JWH, Wang J, Jing D, and Mi JQ
- Subjects
- Animals, Humans, Mice, Gene Expression Regulation, Leukemic, Enhancer Elements, Genetic, Eosinophilia genetics, Eosinophilia metabolism, Eosinophilia pathology, ETS Translocation Variant 6 Protein, Interleukin-3 genetics, Interleukin-3 metabolism, Oncogene Proteins, Fusion genetics, Oncogene Proteins, Fusion metabolism, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology, Precursor Cell Lymphoblastic Leukemia-Lymphoma metabolism, Proto-Oncogene Proteins c-ets genetics, Proto-Oncogene Proteins c-ets metabolism, Repressor Proteins genetics, Repressor Proteins metabolism, Translocation, Genetic
- Abstract
ETV6::ACSL6 represents a rare genetic aberration in hematopoietic neoplasms and is often associated with severe eosinophilia, which confers an unfavorable prognosis requiring additional anti-inflammatory treatment. However, since the translocation is unlikely to produce a fusion protein, the mechanism of ETV6::ACSL6 action remains unclear. Here, we performed multi-omics analyses of primary leukemia cells and patient-derived xenografts from an acute lymphoblastic leukemia (ALL) patient with ETV6::ACSL6 translocation. We identified a super-enhancer located within the ETV6 gene locus, and revealed translocation and activation of the super-enhancer associated with the ETV6::ACSL6 fusion. The translocated super-enhancer exhibited intense interactions with genomic regions adjacent to and distal from the breakpoint at chromosomes 5 and 12, including genes coding inflammatory factors such as IL-3. This led to modulations in DNA methylation, histone modifications, and chromatin structures, triggering transcription of inflammatory factors leading to eosinophilia. Furthermore, the bromodomain and extraterminal domain (BET) inhibitor synergized with standard-of-care drugs for ALL, effectively reducing IL-3 expression and inhibiting ETV6::ACSL6 ALL growth in vitro and in vivo. Overall, our study revealed for the first time a cis-regulatory mechanism of super-enhancer translocation in ETV6::ACSL6ALL, leading to an ALL-accompanying clinical syndrome. These findings may stimulate novel treatment approaches for this challenging ALL subtype.
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- 2024
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24. Cytogenetic and epidemiological profile of chronic myeloid leukemia in Morocco.
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Benchikh S, Charlène SSG, Bousfiha A, Razoki L, Aboulfaraj J, Zarouf L, Hamouchi AE, Malki A, and Nassereddine S
- Subjects
- Humans, Morocco epidemiology, Male, Female, Middle Aged, Adult, Aged, Adolescent, Young Adult, Child, Cytogenetic Analysis, Translocation, Genetic, Aged, 80 and over, Incidence, Child, Preschool, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive epidemiology, Leukemia, Myelogenous, Chronic, BCR-ABL Positive diagnosis
- Abstract
Chronic myeloid leukemia (CML) is a neoplastic disease of genetic origin resulting from clonal proliferation of hematopoietic stem cells (HSCs). The reciprocal translocation t(9;22)(q34;q11) is the main chromosomal abnormality involved in this pathology, usually detected by conventional cytogenetics. This article aims to investigate the epidemiological, cytogenetic, therapeutic, and clinical characteristics of Moroccan patients with CML. This research represents the first large-scale study of CML patients in Morocco and was carried out at Institut Pasteur of Morocco. Bone marrow samples were processed for cytogenetic analysis, and karyotypes were described according to an international system of human cytogenetic nomenclature (ISCN 2016). Patients were studied according to their epidemiological characteristics, clinical information and cytogenetic results. For statistical calculations, R version 4.3.1 was used to analyze the data and calculate the statistical parameters. RStudio and Power BI were used for data visualization. The National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) method of incidence estimation was used to calculate our incidence. We received 826 patients (from 1992 to 2023) who were referred for suspected CML or who were undergoing treatment. Only 650 patients with confirmed CML were included in the study, all of whom underwent their first cytogenetic test. The median age of our patients was 45 years and the sex ratio was 1.03. At the time of diagnosis, 147 (30%) of the patients had clinical manifestations. Most patients were diagnosed in the chronic phase (94.5%). Nineteen complex variant translocations of the Philadelphia (Ph) chromosome were detected. At the time of diagnosis, 55 (11.5%) patients had ACAs, of which 30 (54.5%) were high-risk ACAs. Based on data from 174 patients treated with imatinib, the median time to complete cytogenetic response (CCyR) was 11 months, and at the last cytogenetic follow-up, 81 patients (46.6%) achieved CCyR, while 64 patients (36.8%) showed no response to treatment. Regarding adherence to European LeukemiaNet (ELN) guidelines, 58 patients (33%) were followed according to these guidelines, with optimal treatment in 8.6%, suboptimal treatment in 7% and treatment failure in 18%. The estimated incidence of chronic myeloid leukemia calculated is 0.6 cases per 100,000 in the Casablanca region. This study provides a detailed overview of CML in Morocco, highlighting important clinical, cytogenetic and therapeutic aspects despite some limitations. It also highlights the need to deepen our understanding of this complex disease for disease management in our specific context., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
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- 2024
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25. Two recurrent types of IGH ::5' BCL2 breakpoints representing cytogenetic ins(14;18)(q32;q21q21) and t(14;18)(q32;q21), mediated by the VDJ and class switch recombination processes, respectively.
- Author
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Maekawa F, Hayashida M, Takeoka K, Fukutsuka K, Nakagawa M, Akasaka T, Sakamoto S, Sumiyoshi S, Kobashi Y, and Ohno H
- Subjects
- Humans, Immunoglobulin Class Switching genetics, V(D)J Recombination genetics, Lymphoma, Follicular genetics, Lymphoma, Follicular pathology, Middle Aged, Male, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell diagnosis, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Female, In Situ Hybridization, Fluorescence, Aged, Chromosomes, Human, Pair 14 genetics, Translocation, Genetic, Chromosomes, Human, Pair 18 genetics, Immunoglobulin Heavy Chains genetics, Proto-Oncogene Proteins c-bcl-2 genetics, Chromosome Breakpoints
- Abstract
We describe two types of IGH :: BCL2 breakpoints involving the 5' region of BCL2 (5' BCL2 ). One was ins(14;18)(q32;q21q21) observed in 2 follicular lymphoma (FL) cases, in which IGH was cleaved at 3' of IGHD and 5' of IGHJ and BCL2 was cleaved at 5' BCL2 and downstream regions, and a 281- or 201-kilobase pair fragment containing the BCL2 protein-coding sequences was invertedly inserted into IGH . In another type observed in 2 FL and 2 chronic lymphocytic leukemia (CLL) cases, breakage and reunion occurred within the switch region associated with IGHM (Sµ) and 5' BCL2 , creating IGH Sµ::5' BCL2 fusion sequences on der(18)t(14;18)(q32;q21). The former is considered to be mediated by VDJ -recombination, while the latter by the class switch recombination process. There were no particular features in FL or CLL cases with IGH ::5' BCL2 breakpoints compared with those with t(14;18)(q32;q21)/ IGH :: BCL2 involving the 3' breakpoint cluster regions.
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- 2024
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26. Modeling and therapeutic targeting of t(8;21) AML with/without TP53 deficiency.
- Author
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Zhang W, Li J, Yamamoto K, and Goyama S
- Subjects
- Animals, Mice, Humans, Oncogene Proteins, Fusion genetics, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute therapy, Leukemia, Myeloid, Acute etiology, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 deficiency, Chromosomes, Human, Pair 8 genetics, Translocation, Genetic, Chromosomes, Human, Pair 21 genetics, Disease Models, Animal, Core Binding Factor Alpha 2 Subunit genetics, Core Binding Factor Alpha 2 Subunit deficiency
- Abstract
Acute myeloid leukemia (AML) with t(8;21)(q22;q22.1);RUNX1-ETO is one of the most common subtypes of AML. Although t(8;21) AML has been classified as favorable-risk, only about half of patients are cured with current therapies. Several genetic abnormalities, including TP53 mutations and deletions, negatively impact survival in t(8;21) AML. In this study, we established Cas9
+ mouse models of t(8;21) AML with intact or deficient Tpr53 (a mouse homolog of TP53) using a retrovirus-mediated gene transfer and transplantation system. Trp53 deficiency accelerates the in vivo development of AML driven by RUNX1-ETO9a, a short isoform of RUNX1-ETO with strong leukemogenic potential. Trp53 deficiency also confers resistance to genetic depletion of RUNX1 and a TP53-activating drug in t(8;21) AML. However, Trp53-deficient t(8;21) AML cells were still sensitive to several drugs such as dexamethasone. Cas9+ RUNX1-ETO9a cells with/without Trp53 deficiency can produce AML in vivo, can be cultured in vitro for several weeks, and allow efficient gene depletion using the CRISPR/Cas9 system, providing useful tools to advance our understanding of t(8;21) AML., (© 2024. The Author(s).)- Published
- 2024
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27. Does presence of complex translocations involving BCR::ABL1 in chronic myeloid leukemia affect the response rate to tyrosine kinase inhibitors? A systematic review of the literature.
- Author
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Sharma D, Wilson C, Kumar S, Ghose S, Sahoo R, and Sharawat SK
- Subjects
- Humans, Middle Aged, Philadelphia Chromosome, Treatment Outcome, Male, Female, Tyrosine Kinase Inhibitors, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive pathology, Translocation, Genetic, Protein Kinase Inhibitors therapeutic use, Fusion Proteins, bcr-abl genetics
- Abstract
Philadelphia (Ph) chromosome (9;22)(q34;q11) comprises 90-95 % of chronic myeloid leukemia (CML), while 5-10 % of CML have translocations involving three or more chromosomes. The outcome of treating patients harbouring complex Ph-positive cytogenetics with tyrosine kinase inhibitors (TKI) is unclear. In the present systematic review, we aim to summarise the response of patients with complex Ph-positive cytogenetics to treatment with TKI therapy. We collated all available literature from databases such as PubMed, Google Scholar, Web of Science database, Cochrane library, Scopus and Embase (up until January 31st, 2024), which describe cases of patients with CML, harbouring complex Ph-positive variations (three and four-way translocations), and summarised their response to TKI therapy. The studies were screened for the following criteria: documented TKI intervention and outcome (whether CR was achieved). Studies that did not report the same, were excluded. Additionally, we report a case from our center of a 55-year-old patient with CML, positive for the Ph-chromosome, harbouring a three-way translocation involving chromosome 15 i.e. 46XX, t(9;15;22) (q34;p11;q11). Identification of BCR::ABL and involvement of chromosome 15 was carried out using conventional cytogenetics, fluorescence in situ hybridization (FISH), and quantitative PCR (qPCR). Based on the inclusion criteria, a total of 15 studies were included from which a total of 87 cases were covered. Overall, we identified 38 unique complex three- and four-way translocations across 87 Ph-positive cases and found that 85 patients with complex Ph-positive cytogenetics achieved complete remission upon treatment and did not appear to have a lesser response to TKI therapy., Competing Interests: Declaration of competing interest The authors don't have any conflicts of interest to disclose., (Copyright © 2024. Published by Elsevier Inc.)
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- 2024
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28. Molecular Cytogenetic Characterization of Novel Wheat-Rye T1RS.1AL Translocation Lines with Resistance to Powdery Mildew and Stripe Rust Derived from the Chinese Rye Landrace Qinling.
- Author
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Li Z, Sun Z, Zhao L, Yan T, Ren Z, and Ren T
- Subjects
- In Situ Hybridization, Fluorescence, East Asian People, Triticum genetics, Triticum microbiology, Triticum immunology, Secale genetics, Secale microbiology, Plant Diseases microbiology, Plant Diseases immunology, Plant Diseases genetics, Translocation, Genetic, Disease Resistance genetics, Ascomycota physiology, Basidiomycota physiology, Chromosomes, Plant genetics
- Abstract
Stripe rust and powdery mildew are serious diseases that severely decrease the yield of wheat. Planting wheat cultivars with powdery mildew and stripe rust resistance genes is the most effective way to control these two diseases. Introducing disease resistance genes from related species into the wheat genome via chromosome translocation is an important way to improve wheat disease resistance. In this study, nine novel T1RS.1AL translocation lines were developed from the cross of wheat cultivar Chuannong25 (CN25) and a Chinese rye Qinling. The results of non-denaturing fluorescence in situ hybridization and PCR showed that all new lines were homozygous for the T1RS.1AL translocation. These new T1RS.1AL translocation lines exhibited strong resistance to stripe rust and powdery mildew. The cytogenetics results indicated that the resistance of the new lines was conferred by the 1RS chromosome arms, which came from Qinling rye. The genetic analysis indicated that there were new dominant resistance genes on the 1RS chromosome arm resistant to stripe rust and powdery mildew, and their resistance patterns were different from those of Yr9, Pm8 , and Pm17 genes. In addition, the T1RS.1AL translocation lines generally exhibited better agronomic traits in the field relative to CN25. These T1RS.1AL translocations have great potential in wheat-breeding programs in the future., Competing Interests: The author(s) declare no conflict of interest.
- Published
- 2024
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29. Increased AID results in mutations at the CRLF2 locus implicated in Latin American ALL health disparities.
- Author
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Rangel V, Sterrenberg JN, Garawi A, Mezcord V, Folkerts ML, Calderon SE, Garcia YE, Wang J, Soyfer EM, Eng OS, Valerin JB, Tanjasiri SP, Quintero-Rivera F, Seldin MM, Masri S, Frock RL, Fleischman AG, and Pannunzio NR
- Subjects
- Humans, DNA Breaks, Double-Stranded, B-Lymphocytes metabolism, B-Lymphocytes immunology, Health Status Disparities, Translocation, Genetic, Genetic Loci, Latin America, Female, Cytidine Deaminase genetics, Mutation, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Hispanic or Latino genetics, Receptors, Cytokine genetics
- Abstract
Activation-induced cytidine deaminase (AID) is a B cell-specific mutator required for antibody diversification. However, it is also implicated in the etiology of several B cell malignancies. Evaluating the AID-induced mutation load in patients at-risk for certain blood cancers is critical in assessing disease severity and treatment options. We have developed a digital PCR (dPCR) assay that allows us to quantify mutations resulting from AID modification or DNA double-strand break (DSB) formation and repair at sites known to be prone to DSBs. Implementation of this assay shows that increased AID levels in immature B cells increase genome instability at loci linked to chromosomal translocation formation. This includes the CRLF2 locus that is often involved in translocations associated with a subtype of acute lymphoblastic leukemia (ALL) that disproportionately affects Hispanics, particularly those with Latin American ancestry. Using dPCR, we characterize the CRLF2 locus in B cell-derived genomic DNA from both Hispanic ALL patients and healthy Hispanic donors and found increased mutations in both, suggesting that vulnerability to DNA damage at CRLF2 may be driving this health disparity. Our ability to detect and quantify these mutations will potentiate future risk identification, early detection of cancers, and reduction of associated cancer health disparities., (© 2024. The Author(s).)
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- 2024
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30. G-Banding and Molecular Cytogenetics Detect Novel Translocations and Cryptic Aberrations in Human Immortal Endothelial Cells.
- Author
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Binz RL and Pathak R
- Subjects
- Humans, Cytogenetic Analysis methods, Endothelial Cells metabolism, Chromosome Aberrations, A549 Cells, Translocation, Genetic, In Situ Hybridization, Fluorescence methods, Human Umbilical Vein Endothelial Cells metabolism, Chromosome Banding
- Abstract
Endothelial cells (ECs) maintain vessel tone and barrier integrity, regulate blood homeostasis, and prevent the extravasation of leukocytes under normal physiological conditions. Because of the limited lifespans and batch-to-batch differences with respect to the genetic make-up of primary ECs, established immortal EC lines are extensively used for studying endothelial biology. To address this issue, the immortal endothelial cell line EA.hy926 was developed by fusing primary human umbilical vein endothelial cells (HUVECs) with human lung carcinoma A549 cells. EA.hy926 cells share a number of similar endothelial properties with HUVECs and are considered the immortal counterpart to primary HUVECs. However, the cytogenetic integrity of EA.hy926 cells is not fully elucidated. We characterized EA.hy926 cells with conventional G-banding and molecular cytogenetic techniques such as spectral karyotyping and subtelomeric fluorescence in situ hybridization. Cytogenetic analysis revealed an array of numerical and stable structural chromosomal rearrangements including one deletion, one duplication, one isochromosome, seven simple translocations, and five complex translocations in Ea.hy926 cells. These findings will advance comprehension of EA.hy926 cell biology and augment future endothelial studies, specifically in comparison studies between HUVECs and EA.hy926 cells.
- Published
- 2024
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31. UnSETtling energy dependence of t(4;14) MM.
- Author
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Bergsagel PL and Chesi M
- Subjects
- Humans, Chromosomes, Human, Pair 4 genetics, Chromosomes, Human, Pair 14 genetics, Chromosomes, Human, Pair 14 ultrastructure, Translocation, Genetic, Energy Metabolism, Male, Female, Multiple Myeloma genetics, Multiple Myeloma pathology
- Published
- 2024
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32. NSD2 drives t(4;14) myeloma cell dependence on adenylate kinase 2 by diverting one-carbon metabolism to the epigenome.
- Author
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Sobh A, Encinas E, Patel A, Surapaneni G, Bonilla E, Kaestner C, Poullard J, Clerio M, Vasan K, Freeman T, Lv D, Dupéré-Richer D, Riva A, Barwick BG, Zhou D, Boise LH, Mitsiades CS, Kim B, Bennett RL, Chandel NS, and Licht JD
- Subjects
- Humans, Chromosomes, Human, Pair 14 genetics, Epigenome, Chromosomes, Human, Pair 4 genetics, Carbon metabolism, Cell Line, Tumor, Repressor Proteins, Multiple Myeloma genetics, Multiple Myeloma metabolism, Multiple Myeloma pathology, Histone-Lysine N-Methyltransferase genetics, Histone-Lysine N-Methyltransferase metabolism, Translocation, Genetic, Adenylate Kinase metabolism, Adenylate Kinase genetics
- Abstract
Abstract: Chromosomal translocation (4;14), an adverse prognostic factor in multiple myeloma (MM), drives overexpression of the histone methyltransferase nuclear receptor binding SET domain protein 2 (NSD2). A genome-wide CRISPR screen in MM cells identified adenylate kinase 2 (AK2), an enzyme critical for high-energy phosphate transfer from the mitochondria, as an NSD2-driven vulnerability. AK2 suppression in t(4;14) MM cells decreased nicotinamide adenine dinucleotide phosphate (NADP[H]) critical for conversion of ribonucleotides to deoxyribonucleosides, leading to replication stress, DNA damage, and apoptosis. Driving a large genome-wide increase in chromatin methylation, NSD2 overexpression depletes S-adenosylmethionine, compromising the synthesis of creatine from its precursor, guanidinoacetate. Creatine supplementation restored NADP(H) levels, reduced DNA damage, and rescued AK2-deficient t(4;14) MM cells. As the creatine phosphate shuttle constitutes an alternative means for mitochondrial high-energy phosphate transport, these results indicate that NSD2-driven creatine depletion underlies the hypersensitivity of t(4;14) MM cells to AK2 loss. Furthermore, AK2 depletion in t(4;14) cells impaired protein folding in the endoplasmic reticulum, consistent with impaired use of mitochondrial adenosine triphosphate (ATP). Accordingly, AK2 suppression increased the sensitivity of MM cells to proteasome inhibition. These findings delineate a novel mechanism in which aberrant transfer of carbon to the epigenome creates a metabolic vulnerability, with direct therapeutic implications for t(4;14) MM., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)
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- 2024
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33. Integrative single-cell analysis of longitudinal t(8;21) AML reveals heterogeneous immune cell infiltration and prognostic signatures.
- Author
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Li XP, Song JT, Dai YT, Zhang WN, Zhao BT, Mao JY, Gao Y, Jiang L, and Liang Y
- Subjects
- Humans, Prognosis, Lymphocytes, Tumor-Infiltrating immunology, Lymphocytes, Tumor-Infiltrating metabolism, Male, Female, Translocation, Genetic, Chromosomes, Human, Pair 21 genetics, CD8-Positive T-Lymphocytes immunology, Adult, Middle Aged, Biomarkers, Tumor genetics, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute immunology, Leukemia, Myeloid, Acute mortality, Leukemia, Myeloid, Acute therapy, Single-Cell Analysis methods, Tumor Microenvironment immunology, Tumor Microenvironment genetics, Chromosomes, Human, Pair 8 genetics
- Abstract
Introduction: Immunotherapies targeting T cells in solid cancers are revolutionizing clinical treatment. Novel immunotherapies have had extremely limited benefit for acute myeloid leukemia (AML). Here, we characterized the immune microenvironment of t(8;21) AML patients to determine how immune cell infiltration status influenced prognosis., Methods: Through multi-omics studies of primary and longitudinal t(8;21) AML samples, we characterized the heterogeneous immune cell infiltration in the tumor microenvironment and their immune checkpoint gene expression. Further external cohorts were also included in this research., Results: CD8+ T cells were enriched and HAVCR2 and TIGIT were upregulated in the CD34
+ CD117dim %-High group; these features are known to be associated with immune exhaustion. Data integration analysis of single-cell dynamics revealed that a subset of T cells (cluster_2) (highly expressing GZMB, NKG7, PRF1 and GNLY ) evolved and expanded markedly in the drug-resistant stage after relapse. External cohort analysis confirmed that the cluster_2 T-cell signature could be utilized to stratify patients by overall survival outcome., Discussion: In conclusion, we discovered a distinct T-cell signature by scRNA-seq that was correlated with disease progression and drug resistance. Our research provides a novel system for classifying patients based on their immune microenvironment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Li, Song, Dai, Zhang, Zhao, Mao, Gao, Jiang and Liang.)- Published
- 2024
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34. The rate of W chromosome degeneration across multiple avian neo-sex chromosomes.
- Author
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Sigeman H, Downing PA, Zhang H, and Hansson B
- Subjects
- Animals, Male, Female, Phylogeny, Songbirds genetics, Translocation, Genetic, Sex Chromosomes genetics, Evolution, Molecular
- Abstract
When sex chromosomes evolve recombination suppression, the sex-limited chromosome (Y/W) commonly degenerate by losing functional genes. The rate of Y/W degeneration is believed to slow down over time as the most essential genes are maintained by purifying selection, but supporting data are scarce especially for ZW systems. Here, we study W degeneration in Sylvioidea songbirds where multiple autosomal translocations to the sex chromosomes, and multiple recombination suppression events causing separate evolutionary strata, have occurred during the last ~ 28.1-4.5 million years (Myr). We show that the translocated regions have maintained 68.3-97.7% of their original gene content, compared to only 4.2% on the much older ancestral W chromosome. By mapping W gene losses onto a dated phylogeny, we estimate an average gene loss rate of 1.0% per Myr, with only moderate variation between four independent lineages. Consistent with previous studies, evolutionarily constrained and haploinsufficient genes were preferentially maintained on W. However, the gene loss rate did not show any consistent association with strata age or with the number of W genes at strata formation. Our study provides a unique account on the pace of W gene loss and reinforces the significance of purifying selection in maintaining essential genes on sex chromosomes., (© 2024. The Author(s).)
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- 2024
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35. An Integrated Transcriptomics and Genomics Approach Detects an X/Autosome Translocation in a Female with Duchenne Muscular Dystrophy.
- Author
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Segarra-Casas A, Yépez VA, Demidov G, Laurie S, Esteve-Codina A, Gagneur J, Parkhurst Y, Muni-Lofra R, Harris E, Marini-Bettolo C, Straub V, and Töpf A
- Subjects
- Humans, Female, DNA Copy Number Variations, Exome Sequencing, Transcriptome genetics, Chromosomes, Human, Pair 17 genetics, Muscular Dystrophy, Duchenne genetics, Muscular Dystrophy, Duchenne diagnosis, Translocation, Genetic, Dystrophin genetics, Chromosomes, Human, X genetics, Genomics methods
- Abstract
Duchenne and Becker muscular dystrophies, caused by pathogenic variants in DMD , are the most common inherited neuromuscular conditions in childhood. These diseases follow an X-linked recessive inheritance pattern, and mainly males are affected. The most prevalent pathogenic variants in the DMD gene are copy number variants (CNVs), and most patients achieve their genetic diagnosis through Multiplex Ligation-dependent Probe Amplification (MLPA) or exome sequencing. Here, we investigated a female patient presenting with muscular dystrophy who remained genetically undiagnosed after MLPA and exome sequencing. RNA sequencing (RNAseq) from the patient's muscle biopsy identified an 85% reduction in DMD expression compared to 116 muscle samples included in the cohort. A de novo balanced translocation between chromosome 17 and the X chromosome (t(X;17)(p21.1;q23.2)) disrupting the DMD and BCAS3 genes was identified through trio whole genome sequencing (WGS). The combined analysis of RNAseq and WGS played a crucial role in the detection and characterisation of the disease-causing variant in this patient, who had been undiagnosed for over two decades. This case illustrates the diagnostic odyssey of female DMD patients with complex structural variants that are not detected by current panel or exome sequencing analysis.
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- 2024
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36. SOX11 expression is restricted to EBV-negative Burkitt lymphoma and is associated with molecular genetic features.
- Author
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Sureda-Gómez M, Iaccarino I, De Bolòs A, Meyer M, Balsas P, Richter J, Rodríguez ML, López C, Carreras-Caballé M, Glaser S, Nadeu F, Jares P, Clot G, Siciliano MC, Bellan C, Tornambè S, Boccacci R, Leoncini L, Campo E, Siebert R, Amador V, and Klapper W
- Subjects
- Humans, Gene Expression Regulation, Neoplastic, Epstein-Barr Virus Infections genetics, Epstein-Barr Virus Infections complications, Epstein-Barr Virus Infections virology, Mutation, DNA Helicases genetics, DNA Helicases metabolism, Translocation, Genetic, Transcription Factors genetics, Transcription Factors metabolism, Male, Inhibitor of Differentiation Proteins genetics, Inhibitor of Differentiation Proteins metabolism, Nuclear Proteins, Burkitt Lymphoma genetics, Burkitt Lymphoma virology, Burkitt Lymphoma metabolism, Burkitt Lymphoma pathology, SOXC Transcription Factors genetics, SOXC Transcription Factors metabolism, Herpesvirus 4, Human genetics
- Abstract
Abstract: SRY-related HMG-box gene 11 (SOX11) is a transcription factor overexpressed in mantle cell lymphoma (MCL), a subset of Burkitt lymphomas (BL) and precursor lymphoid cell neoplasms but is absent in normal B cells and other B-cell lymphomas. SOX11 has an oncogenic role in MCL but its contribution to BL pathogenesis remains uncertain. Here, we observed that the presence of Epstein-Barr virus (EBV) and SOX11 expression were mutually exclusive in BL. SOX11 expression in EBV-negative (EVB-) BL was associated with an IG∷MYC translocation generated by aberrant class switch recombination, whereas in EBV-negative (EBV-)/SOX11-negative (SOX11-) tumors the IG∷MYC translocation was mediated by mistaken somatic hypermutations. Interestingly, EBV- SOX11-expressing BL showed higher frequency of SMARCA4 and ID3 mutations than EBV-/SOX11- cases. By RNA sequencing, we identified a SOX11-associated gene expression profile, with functional annotations showing partial overlap with the SOX11 transcriptional program of MCL. Contrary to MCL, no differences on cell migration or B-cell receptor signaling were found between SOX11- and SOX11-positive (SOX11+) BL cells. However, SOX11+ BL showed higher adhesion to vascular cell adhesion molecule 1 (VCAM-1) than SOX11- BL cell lines. Here, we demonstrate that EBV- BL comprises 2 subsets of cases based on SOX11 expression. The mutual exclusion of SOX11 and EBV, and the association of SOX11 with a specific genetic landscape suggest a role of SOX11 in the early pathogenesis of BL., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)
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- 2024
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37. Exploring G-quadruplex structure in PRCC-TFE3 fusion oncogene: Plausible use as anti cancer therapy for translocation Renal cell carcinoma (tRCC).
- Author
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Neha N and Das P
- Subjects
- Humans, HEK293 Cells, Circular Dichroism, Aminoquinolines, Neoplasm Proteins, Picolinic Acids, Cell Cycle Proteins, G-Quadruplexes, Carcinoma, Renal Cell genetics, Carcinoma, Renal Cell drug therapy, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors genetics, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors metabolism, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors chemistry, Kidney Neoplasms genetics, Kidney Neoplasms drug therapy, Kidney Neoplasms metabolism, Kidney Neoplasms pathology, Oncogene Proteins, Fusion genetics, Translocation, Genetic
- Abstract
The TFE3 fusion gene, byproduct of Xp11.2 translocation, is the diagnostic marker for translocation renal cell carcinoma (tRCC). Absence of any clinically recognized therapy for tRCC, pressing a need to create novel and efficient therapeutic approaches. Previous studies shown that stabilization of the G-quadruplex structure in oncogenes suppresses their expression machinery. To combat the oncogenesis caused by fusion genes, our objective is to locate and stabilize the G-quadruplex structure within the PRCC-TFE3 fusion gene. Using the Quadruplex-forming G Rich Sequences (QGRS) mapper and the Non-B DNA motif search tool (nBMST) online server, we found putative G-quadruplex forming sequences (PQS) in the PRCC-TFE3 fusion gene. Circular dichroism demonstrating a parallel G-quadruplex in the targeted sequence. Fluorescence and UV-vis spectroscopy results suggest that pyridostatin binds to this newly discovered G-quadruplex. The PCR stop assay, as well as transcriptional or translational inhibition using real time PCR and Dual luciferase assay, revealed that stable G-quadruplex formation affects biological processes. Confocal microscopy of HEK293T cells transfected with the fusion transcript confirmed G-quadruplexes formation in cell. This investigation may shed light on G-quadruplex's functions in fusion genes and may help in the development of therapies specifically targeted against fusion oncogenes, which would enhance the capability of current tRCC therapy approach., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)
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- 2024
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38. [Primary nasal and sinus blastic plasmacytoid dendritic cell neoplasm with EWSR1 gene translocation: report of a case].
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Ma TY, Jing YL, Li YH, and Liu HG
- Subjects
- Humans, Female, Adult, RNA-Binding Proteins genetics, RNA-Binding Proteins metabolism, Paranasal Sinus Neoplasms genetics, Paranasal Sinus Neoplasms pathology, Chromosomes, Human, Pair 22 genetics, Calmodulin-Binding Proteins genetics, Calmodulin-Binding Proteins metabolism, Translocation, Genetic, RNA-Binding Protein EWS genetics, Dendritic Cells pathology, Nose Neoplasms genetics, Nose Neoplasms pathology, Nose Neoplasms metabolism
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- 2024
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39. [YAP1-KMT2A fused sarcoma: report of a case].
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Yin TC, Fang W, Shao MY, Sun M, Zhao L, I QY, Yu L, and Wang J
- Subjects
- Humans, Female, Adult, Histone-Lysine N-Methyltransferase genetics, Histone-Lysine N-Methyltransferase metabolism, Fibrosarcoma genetics, Fibrosarcoma metabolism, Fibrosarcoma pathology, Translocation, Genetic, Oncogene Proteins, Fusion genetics, Oncogene Proteins, Fusion metabolism, In Situ Hybridization, Fluorescence, Adaptor Proteins, Signal Transducing metabolism, Adaptor Proteins, Signal Transducing genetics, Soft Tissue Neoplasms genetics, Soft Tissue Neoplasms pathology, Soft Tissue Neoplasms metabolism, YAP-Signaling Proteins, Sarcoma genetics, Sarcoma metabolism, Sarcoma pathology, Transcription Factors metabolism, Transcription Factors genetics, Myeloid-Lymphoid Leukemia Protein genetics, Myeloid-Lymphoid Leukemia Protein metabolism
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- 2024
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40. Testing for t(3;8) in MYC/BCL6-rearranged large B-cell lymphoma identifies a high-risk subgroup with inferior survival.
- Author
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Maybury BD, James L, Phillips N, Venkatadasari I, Qureshi I, Riley J, Talbot G, Moosai S, Giles H, Chadderton N, Dowds J, Rakesh P, Crosland H, Haslam A, Lane S, Vega Gonzalez M, Davies D, Cherian G, Shenouda A, Kaudlay P, Starczynski J, Rudzki Z, and Chaganti S
- Subjects
- Humans, Male, Female, Middle Aged, Aged, Prognosis, Gene Rearrangement, Adult, Aged, 80 and over, Oncogene Proteins, Fusion genetics, Proto-Oncogene Proteins c-bcl-6 genetics, Lymphoma, Large B-Cell, Diffuse genetics, Lymphoma, Large B-Cell, Diffuse mortality, Lymphoma, Large B-Cell, Diffuse pathology, Translocation, Genetic, Proto-Oncogene Proteins c-myc genetics
- Abstract
Abstract: A reciprocal t(3;8) BCL6::MYC fusion is common in large B-cell lymphoma (LBCL) with MYC and BCL6 disruption. These pseudo-double-hit cases are not adverse, whereas t(3;8)-MYC/BCL6 lymphoma has an inferior prognosis relative to other MYC-rearranged LBCL., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)
- Published
- 2024
- Full Text
- View/download PDF
41. [Genetic analysis and PGT-SR outcome of a male carrier of exceptional complex chromosome rearrangement].
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Liu D, Dong YQ, Chen CQ, Yu XS, Yan J, Liu FH, and Zhang XQ
- Subjects
- Humans, Male, Female, Karyotyping, Pregnancy, Spermatozoa, Adult, Genetic Testing, Heterozygote, Chromosome Aberrations, Karyotype, High-Throughput Nucleotide Sequencing, Preimplantation Diagnosis methods, Translocation, Genetic
- Abstract
Objective: To investigate the clinical and genetic characteristics of a male carrier of exceptional complex chromosome rearrangement (CCR) and the outcome of preimplantation genetic testing for chromosomal structural rearrangement (PGT-SR)., Methods: Using the modified high resolution G banding technique and whole-genome low-coverage sequencing (WGLCS), we analyzed the cellular karyotype and molecular karyotype of a male carrier of CCR, performed an analysis of the single-sperm chromosome copy number and conducted PGT-SR for the patient by next-generation sequencing (NGS). In addition, we reviewed the literature on reported male carriers of CCRs and summarized their normal/balanced sperm ratios and PGT-SR outcomes., Results: The karyotype of the patient was 46,XY,der(5)inv(5)(q14.3q23.2)t(5;14;11) (q23.2;q31.1;q21),der(11)t(5;14;11);der(14)t(5;14;11), with the translocation breakpoints located in the intergenic region. Single-sperm sequencing revealed 20.0%(7/35)of normal haploids in the male's spermatozoa, and the results PGT-SR showed a proportion of 25.0%(4/16)of normal/balanced embryos. After thawing and transferring of 2 euploid blastocysts, a healthy male infant was successfully delivered., Conclusion: The proportion of normal haploids in the spermatozoa of male CCR carriers may be higher than theoretically predicted, and PGT-SR can effectively improve the pregnancy outcome in male CCR carriers and provide valuable data for genetic counseling.
- Published
- 2024
42. Analysis of Preimplantation and Clinical Outcomes of Two Cases by Oxford Nanopore Sequencing.
- Author
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Ou J, Wang J, Sun J, Ni M, Meng Q, Ding J, Fan H, Feng S, Huang Y, Li H, and Fei J
- Subjects
- Humans, Female, Pregnancy, Adult, Embryo Transfer methods, Male, Preimplantation Diagnosis methods, Nanopore Sequencing methods, Translocation, Genetic
- Abstract
It is challenging to distinguish embryos with a balanced translocation karyotype from a normal karyotype by existing conventional genetic testing methods. However, in germ-cell gamete generation, chromosome exchange and separation through cell meiosis form a different proportion of unbalanced gametes. Adverse birth events may occur, such as repeated miscarriages and fetal birth defects. In this study, the exact breakpoints of structural variation (SV) from two balanced translocation carrier families by using Nanopore long reads sequencing technology were obtained, and haplotype analysis and Sanger verified the accuracy of the detection results, confirming the application value of the Nanopore sequencing technology in the detection of balanced translocation before embryo implantation. Nanopore long-read sequencing was performed to find the precise breakpoint of chromosome-balanced translocation carriers. The breakpoints were subsequently verified by designing primers across the breakpoints and Sanger sequencing. Haplotype linkage analysis of SNPs which can be linked by a read block of families around the breakpoint regions was followed. After frozen (-thawed) embryo transfer (FET), prenatal cytogenetic analysis of amniotic fluid cells confirmed the predicted karyotypes from the transferred embryos. The presence of breakpoints was detected in three embryos of patient 1. No breakpoints were detected in either embryo of patient 2. One balanced translocated embryo from patient 1 and one normal euploid embryo from patient 2 were transplanted back into the patients, and amniotic fluid cells were analyzed for the karyotype of fetuses. The results were entirely consistent with the fetal karyotype. And through late follow-up, both patients successfully had a live birth fetus. The breakpoint location of the balanced chromosome translocation can be accurately found by Nanopore sequencing. The haplotype of carriers can be successfully constructed by Nanopore and sanger sequencing confirmed that the results were accurate. This is very advantageous for preimplantation genetic testing for chromosomal structural rearrangements (PGT-SR) detection in the families without proband., (© 2024. The Author(s), under exclusive licence to Society for Reproductive Investigation.)
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- 2024
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43. Childhood and Adolescent Relapsed/Refractory Aggressive B-Cell Lymphomas With t(8;14) and BCL2 Expression, Burkitt Lymphoma Versus Diffuse Large B-Cell Lymphoma: A Diagnostic Challenge.
- Author
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El Dana F, Garces Narvaez SA, El-Mallawany NK, Agrusa JE, Dreyer ZE, Marcogliese AN, Elghetany MT, Punia JN, Ok CY, Patel KP, Lopez-Terrada DH, Fisher KE, and Curry CV
- Subjects
- Humans, Adolescent, Male, Child, Female, Diagnosis, Differential, Biomarkers, Tumor genetics, Biomarkers, Tumor metabolism, Chromosomes, Human, Pair 14 genetics, Neoplasm Recurrence, Local pathology, Neoplasm Recurrence, Local genetics, Chromosomes, Human, Pair 8 genetics, Burkitt Lymphoma genetics, Burkitt Lymphoma diagnosis, Burkitt Lymphoma pathology, Burkitt Lymphoma metabolism, Burkitt Lymphoma therapy, Lymphoma, Large B-Cell, Diffuse genetics, Lymphoma, Large B-Cell, Diffuse diagnosis, Lymphoma, Large B-Cell, Diffuse pathology, Lymphoma, Large B-Cell, Diffuse therapy, Lymphoma, Large B-Cell, Diffuse metabolism, Proto-Oncogene Proteins c-bcl-2 genetics, Proto-Oncogene Proteins c-bcl-2 metabolism, Translocation, Genetic
- Abstract
We present 2 diagnostically challenging cases of pediatric/adolescent relapsed/refractory aggressive mature B-cell non-Hodgkin lymphoma (B-NHL) within the spectrum of Burkitt lymphoma and diffuse large B-cell lymphoma and illustrate the different therapeutic regimens that are employed for pediatric and adult cancer centers. Both cases displayed varying-sized lymphoma cells with occasional single prominent nucleoli and heterogeneous BCL2 expression. Cytogenetics revealed complex karyotypes with t(8:14)(q24.2;q32) and IGH::MYC rearrangement by FISH. Next generation sequencing revealed deleterious TP53 and MYC mutations. We concluded that both could be diagnosed as "DLBCL-NOS with MYC rearrangement" using the current pathologic classifications, 2022 International Consensus Classification (ICC) and World Health Organization Classifications of Haematolymphoid Tumors (WHO-HAEM5). This report illustrates diagnostic challenges and treatment dilemmas that may be encountered, particularly for adolescent and young adults (AYA)., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
- Published
- 2024
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44. Cytogenetic and Genomic Characterization of a Novel Wheat-Tetraploid Thinopyrum elongatum 1BS⋅1EL Translocation Line with Stripe Rust Resistance.
- Author
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Wu D, Zhao X, Xie Y, Li L, Li Y, Zhu W, Xu L, Wang Y, Zeng J, Cheng Y, Sha L, Fan X, Zhang H, Zhou Y, and Kang H
- Subjects
- Chromosomes, Plant genetics, Basidiomycota physiology, Plant Breeding, In Situ Hybridization, Fluorescence, Polymorphism, Single Nucleotide genetics, Genome, Plant genetics, Triticum microbiology, Triticum genetics, Plant Diseases microbiology, Plant Diseases genetics, Plant Diseases immunology, Disease Resistance genetics, Tetraploidy, Poaceae genetics, Poaceae microbiology, Translocation, Genetic, Puccinia physiology
- Abstract
Stripe rust, caused by Puccinia striiformis f. sp. tritici , is a destructive wheat disease pathogen. Thinopyrum elongatum is a valuable germplasm including diploid, tetraploid, and decaploid with plenty of biotic and abiotic resistance. In a previous study, we generated a stripe rust-resistant wheat-tetraploid Th. elongatum 1E/1D substitution line, K17-841-1. To further apply the wild germplasm for wheat breeding, we selected and obtained a new homozygous wheat-tetraploid Th. elongatum translocation line, T1BS⋅1EL, using genomic in situ hybridization, fluorescence in situ hybridization (FISH), oligo-FISH painting, and the wheat 55K single nucleotide polymorphism genotyping array. The T1BS⋅1EL is highly resistant to stripe rust at the seedling and adult stages. Pedigree and molecular marker analyses revealed that the resistance gene was located on the chromosome arm 1EL of tetraploid Th . elongatum, tentatively named Yr1EL . In addition, we developed and validated 32 simple sequence repeat markers and two kompetitive allele-specific PCR assays that were specific to the tetraploid Th. elongatum chromosome arm 1EL to facilitate marker-assisted selection for alien 1EL stripe rust resistance breeding. This will help us explore and locate the stripe rust resistance gene mapping on the 1E chromosome and deploy it in the wheat breeding program., Competing Interests: The author(s) declare no conflict of interest.
- Published
- 2024
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45. The t(X;20)(q13;q13) translocation is a good prognostic factor in myeloid neoplasms: A report of 25 cases from the Groupe Francophone de Cytogénétique Hématologique.
- Author
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Nguyen-Khac F, Muller M, Chapiro E, Abermil N, Collonge-Rame MA, Daudignon A, Gaillard B, Guzun D, Ittel A, Lefebvre C, Lesesve JF, Mozziconacci MJ, Penther D, Quessada J, Settegrana C, Smagghe L, Terre C, Veronese L, Hirsch P, and Troadec MB
- Subjects
- Humans, Male, Female, Middle Aged, Aged, Adult, Prognosis, Myeloproliferative Disorders genetics, Myeloproliferative Disorders diagnosis, Aged, 80 and over, Translocation, Genetic
- Published
- 2024
- Full Text
- View/download PDF
46. Favorable Outcome of High-grade Endometrial Stromal Sarcoma in an Adolescent.
- Author
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Hu B, Howitt BE, Cizek S, Diver E, Hiniker S, Crane J, Daldrup-Link H, and Spunt SL
- Subjects
- Humans, Female, Adolescent, Translocation, Genetic, Combined Modality Therapy, Prognosis, Fertility Preservation, Sarcoma, Endometrial Stromal pathology, Sarcoma, Endometrial Stromal therapy, Endometrial Neoplasms pathology, Endometrial Neoplasms therapy
- Abstract
High-grade endometrial stromal sarcoma is a rare and aggressive soft tissue tumor characterized by YWHAE::NUTM2A/B translocations, diagnosis at a median of 50-60 years, and a poor prognosis (overall survival 30%-40%). We describe a 16-year-old patient with high-grade endometrial stromal sarcoma and regional nodal and pulmonary metastases who is a long-term survivor after grossly complete tumor resection, intensive chemotherapy, and pelvic radiotherapy. We discovered a previously undescribed YWHAE::NUTM2E translocation in the tumor. Our patient's favorable outcome suggests that intensive multimodality therapy with curative intent is appropriate for young patients with high-grade endometrial stromal sarcoma and highlights the importance of fertility preservation., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)
- Published
- 2024
- Full Text
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47. Comparison of Optical Genome Mapping With Conventional Diagnostic Methods for Structural Variant Detection in Hematologic Malignancies.
- Author
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Shim Y, Koo YK, Shin S, Lee ST, Lee KA, and Choi JR
- Subjects
- Humans, Chromosome Inversion, Translocation, Genetic, Chromosome Mapping, Genome, Human, Genomic Structural Variation
- Abstract
Background: Structural variants (SVs) are currently analyzed using a combination of conventional methods; however, this approach has limitations. Optical genome mapping (OGM), an emerging technology for detecting SVs using a single-molecule strategy, has the potential to replace conventional methods. We compared OGM with conventional diagnostic methods for detecting SVs in various hematologic malignancies., Methods: Residual bone marrow aspirates from 27 patients with hematologic malignancies in whom SVs were observed using conventional methods (chromosomal banding analysis, FISH, an RNA fusion panel, and reverse transcription PCR) were analyzed using OGM. The concordance between the OGM and conventional method results was evaluated., Results: OGM showed concordance in 63% (17/27) and partial concordance in 37% (10/27) of samples. OGM detected 76% (52/68) of the total SVs correctly (concordance rate for each type of SVs: aneuploidies, 83% [15/18]; balanced translocation, 80% [12/15] unbalanced translocation, 54% [7/13] deletions, 81% [13/16]; duplications, 100% [2/2] inversion 100% [1/1]; insertion, 100% [1/1]; marker chromosome, 0% [0/1]; isochromosome, 100% [1/1]). Sixteen discordant results were attributed to the involvement of centromeric/telomeric regions, detection sensitivity, and a low mapping rate and coverage. OGM identified additional SVs, including submicroscopic SVs and novel fusions, in five cases., Conclusions: OGM shows a high level of concordance with conventional diagnostic methods for the detection of SVs and can identify novel variants, suggesting its potential utility in enabling more comprehensive SV analysis in routine diagnostics of hematologic malignancies, although further studies and improvements are required.
- Published
- 2024
- Full Text
- View/download PDF
48. An odd dancing couple. Non-small cell lung carcinoma with coexisting EGFR mutation and NTRK-1 translocation: A case report.
- Author
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Robledano R and Lozano MD
- Subjects
- Humans, Male, Translocation, Genetic, Aged, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung pathology, ErbB Receptors genetics, Lung Neoplasms genetics, Lung Neoplasms pathology, Mutation, Proto-Oncogene Mas, Receptor, trkA genetics
- Abstract
In the 21st century, there has been a dramatic shift in the diagnosis and management of non-small cell lung carcinoma (NSCLC), with an increasing use of minimally invasive tissue acquisition methods. Current treatments require morphologic subtyping and biomarker information in all cases. Determining such biomarkers is a continuously evolving field; current guidelines state that the determination of mutations on the Epidermal Growth Factor (EFGR), Kirsten Rat Sarcoma viral oncogene homolog (KRAS), Proto-oncogene B-Raf (BRAF), Human epidermal growth factor receptor 2 (HER2) and Anaplastic Lymphoma Kinase (ALK), genes as well as fusions on genes such as ROS Proto-Oncogene 1, Receptor Tyrosine Kinase (ROS1), MET proto-oncogene, receptor tyrosine kinase (MET), RET proto-oncogene (RET), and the Neurotrophic Tyrosine Receptor Kinase (NTRK) family is mandatory. While analyzing such alterations, some of them were first reported to be mutually exclusive, although in recent years, it has been shown otherwise in some of these cases. Moreover, so was the case with the concomitant expression of NTRK fusions and EGFR mutations. We present a case report of a patient with concomitant EGFR mutation and NTRK1 fusion., (© 2024 The Authors. Diagnostic Cytopathology published by Wiley Periodicals LLC.)
- Published
- 2024
- Full Text
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49. Proteomic Characterization of Undifferentiated Small Round Cell Sarcomas With EWSR1 and CIC::DUX4 Translocations Reveals Diverging Tumor Biology and Distinct Diagnostic Markers.
- Author
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Doll S, Schweizer L, Bollwein C, Steiger K, Pfarr N, Walker M, Wörtler K, Knebel C, von Eisenhart-Rothe R, Hartmann W, Weichert W, Mann M, Kuhn PH, and Specht K
- Subjects
- Humans, Female, Male, Adult, Adolescent, Young Adult, Soft Tissue Neoplasms genetics, Soft Tissue Neoplasms pathology, Soft Tissue Neoplasms diagnosis, Middle Aged, Oncogene Proteins, Fusion genetics, Bone Neoplasms genetics, Bone Neoplasms pathology, Bone Neoplasms diagnosis, Child, Calmodulin-Binding Proteins genetics, RNA-Binding Proteins genetics, Repressor Proteins genetics, RNA-Binding Protein EWS genetics, Biomarkers, Tumor genetics, Biomarkers, Tumor analysis, Proteomics, Sarcoma, Small Cell genetics, Sarcoma, Small Cell pathology, Sarcoma, Small Cell diagnosis, Translocation, Genetic
- Abstract
Undifferentiated small round cell sarcomas (USRS) of bone and soft tissue are a group of tumors with heterogenic genomic alterations sharing similar morphology. In the present study, we performed a comparative large-scale proteomic analysis of USRS (n = 42) with diverse genomic translocations including classic Ewing sarcomas with EWSR1::FLI1 fusions (n = 24) or EWSR1::ERG fusions (n = 4), sarcomas with an EWSR1 rearrangement (n = 2), CIC::DUX4 fusion (n = 8), as well as tumors classified as USRS with no genetic data available (n = 4). Proteins extracted from formalin-fixed, paraffin-embedded pretherapeutic biopsies were analyzed qualitatively and quantitatively using shotgun mass spectrometry (MS). More than 8000 protein groups could be quantified using data-independent acquisition. Unsupervised hierarchical cluster analysis based on proteomic data allowed stratification of the 42 cases into distinct groups reflecting the different molecular genotypes. Protein signatures that significantly correlated with the respective genomic translocations were identified and used to generate a heatmap of all 42 sarcomas with assignment of cases with unknown molecular genetic data to either the EWSR1- or CIC-rearranged groups. MS-based prediction of sarcoma subtypes was molecularly confirmed in 2 cases where next-generation sequencing was technically feasible. MS also detected proteins routinely used in the immunohistochemical approach for the differential diagnosis of USRS. BCL11B highly expressed in Ewing sarcomas, and BACH2 as well as ETS-1 highly expressed in CIC::DUX4-associated sarcomas, were among proteins identified by the present proteomic study, and were chosen for immunohistochemical confirmation of MS data in our study cohort. Differential expressions of these 3 markers in the 2 genetic groups were further validated in an independent cohort of n = 34 USRS. Finally, our proteomic results point toward diverging signaling pathways in the different USRS subgroups., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
- Full Text
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50. Multiple primary dermatofibrosarcoma protuberans tumors in a single patient with chromosomal microarray analysis: A case report and review.
- Author
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Durgin JS, Whittington CP, Joseph M, Harms PW, Andea AA, Pedersen EA, Smith EH, and Harms KL
- Subjects
- Humans, Male, Chromosomes, Human, Pair 17 genetics, Chromosomes, Human, Pair 22 genetics, Collagen Type I, alpha 1 Chain, In Situ Hybridization, Fluorescence methods, Microarray Analysis methods, Neoplasms, Multiple Primary genetics, Neoplasms, Multiple Primary pathology, Translocation, Genetic, Middle Aged, Dermatofibrosarcoma genetics, Dermatofibrosarcoma pathology, Dermatofibrosarcoma diagnosis, Oncogene Proteins, Fusion genetics, Skin Neoplasms genetics, Skin Neoplasms pathology
- Abstract
Dermatofibrosarcoma protuberans (DFSP) is a cutaneous sarcoma with a high propensity for local invasion and recurrence. Although it is a rare event, the occurrence of multiple tumors in a single patient raises a diagnostic dilemma, as metastatic disease should be differentiated from multiple primary malignant events. In more than 90% of DFSP, a pathogenic t(17;22) translocation leads to the expression of COL1A1::PDGFB fusion transcripts. Karyotype analysis, fluorescence in situ hybridization, and RT-PCR can be useful ancillary studies in detecting this characteristic rearrangement, and sequencing of the fusion transcript can be used to support a clonal origin in metastatic and multifocal disease. However, previous reports have demonstrated variable sensitivity of these assays, in part due to the high sequence variability of the COL1A1::PDGFB fusion. Here, we report a patient who developed two distinct DFSP tumors over the course of 7 years. Chromosomal microarray analysis identified distinctive genomic alterations in the two tumors, supporting the occurrence of multiple primary malignant events., (© 2024 The Authors. Journal of Cutaneous Pathology published by John Wiley & Sons Ltd.)
- Published
- 2024
- Full Text
- View/download PDF
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