Tumor initiation and early tumorigenesis: molecular mechanisms and interventional targets

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

Опубликована: Июнь 18, 2024

Abstract Tumorigenesis is a multistep process, with oncogenic mutations in normal cell conferring clonal advantage as the initial event. However, despite pervasive somatic and expansion tissues, their transformation into cancer remains rare event, indicating presence of additional driver events for progression to an irreversible, highly heterogeneous, invasive lesion. Recently, researchers are emphasizing mechanisms environmental tumor risk factors epigenetic alterations that profoundly influencing early malignant evolution, independently inducing mutations. Additionally, evolution tumorigenesis reflects multifaceted interplay between cell-intrinsic identities various cell-extrinsic exert selective pressures either restrain uncontrolled proliferation or allow specific clones progress tumors. by which induce both intrinsic cellular competency remodel stress facilitate not fully understood. In this review, we summarize genetic, epigenetic, external events, effects on co-evolution transformed cells ecosystem during initiation evolution. A deeper understanding earliest molecular holds promise translational applications, predicting individuals at high-risk developing strategies intercept transformation.

Язык: Английский

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Chromosomal instability as a driver of cancer progression

Nature Reviews Genetics, Год журнала: 2024, Номер 26(1), С. 31 - 46

Опубликована: Июль 29, 2024

Язык: Английский

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Ongoing chromothripsis underpins osteosarcoma genome complexity and clonal evolution

Cell, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

Osteosarcoma is the most common primary cancer of bone, with a peak incidence in children and young adults. Using multi-region whole-genome sequencing, we find that chromothripsis an ongoing mutational process, occurring subclonally 74% osteosarcomas. Chromothripsis generates highly unstable derivative chromosomes, evolution which drives acquisition oncogenic mutations, clonal diversification, intra-tumor heterogeneity across diverse sarcomas carcinomas. In addition, characterize new mechanism, termed loss-translocation-amplification (LTA) chromothripsis, mediates punctuated about half pediatric adult high-grade LTA occurs when single double-strand break triggers concomitant TP53 inactivation oncogene amplification through breakage-fusion-bridge cycles. It particularly prevalent osteosarcoma not detected other cancers driven by mutation. Finally, identify level genome-wide loss heterozygosity as strong prognostic indicator for osteosarcoma.

Язык: Английский

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Chromothripsis-Mediated Small Cell Lung Carcinoma

Cancer Discovery, Год журнала: 2024, Номер 15(1), С. 83 - 104

Опубликована: Авг. 26, 2024

Abstract Small cell lung carcinoma (SCLC) is a highly aggressive malignancy that typically associated with tobacco exposure and inactivation of RB1 TP53 genes. Here, we performed detailed clinicopathologic, genomic, transcriptomic profiling an atypical subset SCLC lacked co-inactivation arose in never/light smokers. We found most cases were chromothripsis—massive, localized chromosome shattering—recurrently involving 11 or 12 resulting extrachromosomal amplification CCND1 co-amplification CCND2/CDK4/MDM2, respectively. Uniquely, these clinically tumors exhibited genomic pathologic links to pulmonary carcinoids, suggesting previously uncharacterized mode pathogenesis via transformation from lower-grade neuroendocrine their progenitors. Conversely, never-smokers harboring inactivated hallmarks adenocarcinoma-to-SCLC derivation, supporting two distinct pathways plasticity-mediated never-smokers. Significance: provide the first description unique lacking RB1/TP53 alterations identify extensive chromothripsis pathogenetic carcinoids as its hallmark features. This work defines novel entity among cancers, highlighting exceptional histogenesis, clinicopathologic characteristics, therapeutic vulnerabilities. See related commentary by Nadeem Drapkin, p. 8

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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Exploring the Intricacies of Antimicrobial Resistance: Understanding Mechanisms, Overcoming Challenges, and Pioneering Innovative Solutions

European Journal of Pharmacology, Год журнала: 2025, Номер unknown, С. 177511 - 177511

Опубликована: Март 1, 2025

Язык: Английский

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The importance of protein domain mutations in cancer therapy

Heliyon, Год журнала: 2024, Номер 10(6), С. e27655 - e27655

Опубликована: Март 1, 2024

Cancer is a complex disease that caused by multiple genetic factors. Researchers have been studying protein domain mutations to understand how they affect the progression and treatment of cancer. These can significantly impact development spread cancer changing structure, function, signalling pathways. As result, there growing interest in these be used as prognostic indicators for prognosis. Recent studies shown provide valuable information about severity patient's response treatment. They may also predict resistance targeted therapy The clinical implications are significant, regarded essential biomarkers oncology. However, additional techniques approaches required characterize changes domains their functional effects. Machine learning other computational tools offer promising solutions this challenge, enabling prediction on structure function. Such predictions aid interpretation information. Furthermore, genome editing like CRISPR/Cas9 has made it possible validate significance mutants more efficiently accurately. In conclusion, hold great promise predictive Overall, considerable research still needed better define molecular heterogeneity resolve challenges remain, so full potential realized.

Язык: Английский

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Aspects and outcomes of surveillance for individuals at high-risk of pancreatic cancer

Familial Cancer, Год журнала: 2024, Номер 23(3), С. 323 - 339

Опубликована: Апрель 15, 2024

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related deaths and associated with poor prognosis. The majority these cancers are detected at late stage, contributing to the bad This underscores need for novel, enhanced early detection strategies improve outcomes. While population-based screening not recommended due relatively low incidence PDAC, surveillance individuals high risk PDAC their increased disease. However, outcomes pancreatic cancer in high-risk sorted out yet. In this review, we will address identification discuss objectives targets surveillance, outline how programs organized, summarize undergoing conclude future perspective on novel developments.

Язык: Английский

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Colorectal carcinogenesis in the Lynch syndromes and familial adenomatous polyposis: trigger events and downstream consequences

Hereditary Cancer in Clinical Practice, Год журнала: 2025, Номер 23(1)

Опубликована: Янв. 23, 2025

Abstract Carcinogenesis encompasses processes that lead to increased mutation rates, enhanced cellular division (tumour growth), and invasive growth. Colorectal cancer (CRC) carcinogenesis in carriers of pathogenic APC ( path_APC ) mismatch repair gene path_MMR variants is initiated by a second hit affecting the corresponding wild-type allele. In carriers, hits result development multiple adenomas, with CRC typically emerging after an additional 20 years. path_MLH1 path_MSH2 formation microscopically detectable, microsatellite unstable (MSI) crypts, from which develops about half over their lifetime, often without progressing through diagnosable adenoma stage. These divergent outcomes reflect distinct functions of. MMR genes. direct consequence stochastic mutations may be occurrence growth before tumour expansion, challenging paradigm must always have non-invasive precursor. contrast other path_ path_PMS2 who receive colonoscopic surveillance exhibit minimal increase incidence. This consistent hybrid model: initial cause adenoma, PMS2 allele drive towards become cancerous MSI. Since all mutational events are stochastic, interventions aimed at preventing or curing should ideally target events. Interventions focused on downstream external factors influence clones survive Darwinian selection. Lynch Syndrome, colonoscopy remove adenomas select for carcinogenetic pathways bypass

Язык: Английский

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Cytogenetics in the management of hematological malignancies: An overview of alternative technologies for cytogenetic characterization

Current Research in Translational Medicine, Год журнала: 2024, Номер 72(3), С. 103440 - 103440

Опубликована: Янв. 13, 2024

Genomic characterization is an essential part of the clinical management hematological malignancies for diagnostic, prognostic and therapeutic purposes. Although CBA FISH are still gold standard in hematology detection CNA SV, some alternative technologies intended to complement their deficiencies or even replace them more less near future. In this article, we provide a technological overview these alternatives. CMA historical well established technique high-resolution CNA. For SV detection, there emerging techniques based on study chromatin conformation ones such as RTMLPA fusion transcripts RNA-seq reveal molecular consequences SV. Comprehensive that detect both most interesting because they all information single examination. Among these, OGM promising higher-solution offers complete solution at contained cost, expense relatively low throughput per machine. WGS remains adaptable solution, with long-read approaches enabling very CAs, but requiring heavy bioinformatics installation high cost. However, development genome-wide CAs allows much better description chromoanagenesis. Therefore, have included review update various existing mechanisms implications, especially prognostic, malignancies.

Язык: Английский

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