The two sides of chromosomal instability: drivers and brakes in cancer

Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)

Опубликована: Март 29, 2024

Abstract Chromosomal instability (CIN) is a hallmark of cancer and associated with tumor cell malignancy. CIN triggers chain reaction in cells leading to chromosomal abnormalities, including deviations from the normal chromosome number or structural changes chromosomes. arises errors DNA replication segregation during division, formation abnormal and/or structure Errors result licensing as well stress, such double-strand breaks stalled forks; meanwhile, stem defects machinery, centrosome amplification, erroneous microtubule–kinetochore attachments, spindle assembly checkpoint, defective sister chromatids cohesion. In cells, deleterious damage, proteotoxic metabolic alteration, cycle arrest, senescence. Paradoxically, despite these negative consequences, one hallmarks found over 90% solid tumors blood cancers. Furthermore, could endow enhanced adaptation capabilities due increased intratumor heterogeneity, thereby facilitating adaptive resistance therapies; however, excessive induce death, “just-right” model for tumors. Elucidating complex nature crucial understanding dynamics tumorigenesis developing effective anti-tumor treatments. This review provides an overview causes consequences CIN, paradox phenomenon that continues perplex researchers. Finally, this explores potential CIN-based therapy.

Язык: Английский

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Scrambling the genome in cancer: causes and consequences of complex chromosome rearrangements

Nature Reviews Genetics, Год журнала: 2023, Номер 25(3), С. 196 - 210

Опубликована: Ноя. 8, 2023

Язык: Английский

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Virology—The next fifty years

Cell, Год журнала: 2024, Номер 187(19), С. 5128 - 5145

Опубликована: Сен. 1, 2024

Язык: Английский

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Most large structural variants in cancer genomes can be detected without long reads

Nature Genetics, Год журнала: 2023, Номер 55(12), С. 2139 - 2148

Опубликована: Ноя. 9, 2023

Abstract Short-read sequencing is the workhorse of cancer genomics yet thought to miss many structural variants (SVs), particularly large chromosomal alterations. To characterize missing SVs in short-read whole genomes, we analyzed ‘loose ends’—local violations mass balance between adjacent DNA segments. In landscape loose ends across 1,330 high-purity most (>10-kb) clonal were fully resolved by short reads 87% human genome where copy number could be reliably measured. Some represent neotelomeres, which propose as a hallmark alternative lengthening telomeres phenotype. These pan-cancer findings confirmed long-molecule profiles 38 breast and melanoma cases. Our results indicate that aberrant homologous recombination unlikely drive majority SVs. Furthermore, analysis data provides surprisingly complete picture structure.

Язык: Английский

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Epstein–Barr Viruses: Their Immune Evasion Strategies and Implications for Autoimmune Diseases

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(15), С. 8160 - 8160

Опубликована: Июль 26, 2024

Epstein-Barr virus (EBV), a member of the γ-herpesvirus family, is one most prevalent and persistent human viruses, infecting up to 90% adult population globally. EBV's life cycle includes primary infection, latency, lytic reactivation, with primarily B cells epithelial cells. This has evolved sophisticated strategies evade both innate adaptive immune responses, thereby maintaining lifelong presence within host. persistence facilitated by expression latent genes such as EBV nuclear antigens (EBNAs) membrane proteins (LMPs), which play crucial roles in viral latency oncogenesis. In addition their well-known several types cancer, including nasopharyngeal carcinoma B-cell lymphomas, recent studies have identified pathogenic autoimmune diseases multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus. review highlights intricate interactions between host system, underscoring need for further research develop effective therapeutic preventive against EBV-associated diseases.

Язык: Английский

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C9orf72 expansion creates the unstable folate-sensitive fragile site FRA9A

Deleted Journal, Год журнала: 2024, Номер 1(4)

Опубликована: Окт. 1, 2024

Abstract The hyper-unstable Chr9p21 locus, harbouring the interferon gene cluster, oncogenes and C9orf72, is linked to multiple diseases. C9orf72 (GGGGCC)n expansions (C9orf72Exp) are associated with incompletely penetrant amyotrophic lateral sclerosis, frontotemporal dementia autoimmune disorders. C9orf72Exp patients display hyperactive cGAS-STING-linked immune DNA damage responses, but source of immunostimulatory or damaged unknown. Here, we show in pre-symptomatic sclerosis-frontotemporal patient cells brains cause folate-sensitive chromosomal fragile site, FRA9A. FRA9A centers on >33 kb as highly compacted chromatin embedded an 8.2 Mb fragility zone spanning 9p21, encompassing 46 genes, making one largest sites. instability, heightened global- Chr9p-enriched sister-chromatid exchanges, truncated-Chr9s, acentric-Chr9s Chr9-containing micronuclei, providing endogenous sources DNA. Cells from contained a rearranged FRA9A-expressing Chr9 Chr9-wide dysregulated expression. Somatic repeat instability sensitive folate deficiency. Age-dependent can be transferred CNS peripheral tissues transgenic mice, implicating source. Our results highlight unappreciated effects that trigger vitamin-sensitive chromosome fragility, adding structural variations disease-enriched 9p21 likely elsewhere.

Язык: Английский

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Neurotropic Viruses as Acute and Insidious Drivers of Aging

Biomolecules, Год журнала: 2025, Номер 15(4), С. 514 - 514

Опубликована: Апрель 1, 2025

Aging is the result of various compounding stresses that gradually overcome homeostatic regulation cell, resulting in irreversible damage. This manifests as many acute and chronic conditions, most common which are neurodegeneration dementia. Epidemiological studies have shown significant, strong correlations between viral infection neurodegenerative diseases. review overlays characteristics pathogenesis with hallmarks aging to discuss how active latent viruses contribute aging. Through our contextualization myriad basic science papers, we offer explanations for premature via induction stress response pathways. Viruses induce stresses: dysregulated homeostasis by exogenous proteins overwhelmed protein quality control mechanisms, DNA damage through direct integration epigenetic manipulation, immune-mediated oxidative immune exhaustion, general energy theft amplified an system. Overall, this highlights long-term importance vaccines antivirals addition their benefits.

Язык: Английский

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Integrated genetic analyses of immunodeficiency-associated Epstein-Barr virus- (EBV) positive primary CNS lymphomas

Acta Neuropathologica, Год журнала: 2023, Номер 146(3), С. 499 - 514

Опубликована: Июль 26, 2023

Abstract Immunodeficiency-associated primary CNS lymphoma (PCNSL) represents a distinct clinicopathological entity, which is typically Epstein-Barr virus-positive (EBV + ) and carries an inferior prognosis. Genetic alterations that characterize EBV-related lymphomagenesis remain unclear precluding molecular classification targeted therapies. In this study, comprehensive genetic analysis of 22 EBV PCNSL, therefore, integrated clinical pathological information with exome RNA sequencing (RNASeq) data. PCNSL germline controls carried median 55 protein-coding single nucleotide variants (SNVs; range 24–217) 2 insertions/deletions (range 0–22). landscape was largely shaped by aberrant somatic hypermutation 41.01% 31.79–53.49%) SNVs mapping to its target motifs. Tumors lacked established (MYD88, CD79B, PIM1) copy number (CDKN2A, HLA loss) driving − PCNSL. Instead, were characterized SOCS1 mutations (26%), predicted disinhibit JAK/STAT signaling, mutually exclusive gain-of-function NOTCH pathway (26%). Copy gains enriched on 11q23.3, locus directly for chromosomal aberrations EBV, includes SIK3 known protect from cytotoxic T-cell responses. Losses covered 5q31.2 (STING), critical sensing viral DNA, 17q11 (NF1). Unsupervised clustering RNASeq data revealed two transcriptional groups, shared strong expression CD70 IL1R2, previously linked tolerogenic tumor microenvironments. Correspondingly, deconvolution bulk elevated M2-macrophage, T-regulatory cell, mast cell monocyte fractions in addition novel insights into the pathobiology provide rationale exploration therapies including JAK-, NOTCH- CD70-directed approaches.

Язык: Английский

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The viral etiology of EBV-associated gastric cancers contributes to their unique pathology, clinical outcomes, treatment responses and immune landscape

Frontiers in Immunology, Год журнала: 2024, Номер 15

Опубликована: Март 26, 2024

Epstein-Barr virus (EBV) is a pathogen known to cause number of malignancies, often taking years for them develop after primary infection. EBV-associated gastric cancer (EBVaGC) one such malignancy, and an immunologically, molecularly pathologically distinct entity from EBV-negative (EBVnGC). In comparison with EBVnGCs, EBVaGCs overexpress immune regulatory genes help form immunosuppressive tumor microenvironment (TME), have improved prognosis, overall “immune-hot” phenotype. This review provides overview the histopathology, clinical features outcomes EBVaGCs. We also summarize differences between TMEs which includes significant in cell composition infiltration. A list available EBVaGC EBVnGC gene expression datasets computational tools are provided within this review. Finally, various chemo- immuno-therapeutics treating cancers (GCs), focus on

Язык: Английский

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Targeting EBV Episome for Anti-Cancer Therapy: Emerging Strategies and Challenges

Viruses, Год журнала: 2025, Номер 17(1), С. 110 - 110

Опубликована: Янв. 15, 2025

As a ubiquitous human pathogen, the Epstein–Barr virus (EBV) has established lifelong persistent infection in about 95% of adult population. The EBV is associated with approximately 200,000 cancer cases and 140,000 deaths per year. presence tumor cells provides unique advantage targeting viral genome (also known as episome), to develop anti-cancer therapeutics. In this review, we summarize current strategies episome cells. We also highlight emerging technologies, such clustered regularly interspersed short palindromic repeat (CRISPR)-based gene editing or activation, which offer promising avenues for selective therapy. discuss challenges, limitations, future perspectives these strategies, including potential off-target effects, efficacy safety.

Язык: Английский

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