Pan-cancer whole-genome comparison of primary and metastatic solid tumours

Nature, Journal Year: 2023, Volume and Issue: 618(7964), P. 333 - 341

Published: May 10, 2023

Metastatic cancer remains an almost inevitably lethal disease1-3. A better understanding of disease progression and response to therapies therefore utmost importance. Here we characterize the genomic differences between early-stage untreated primary tumours late-stage treated metastatic using a harmonized pan-cancer analysis (or reanalysis) two unpaired primary4 metastatic5 cohorts 7,108 whole-genome-sequenced tumours. in general have lower intratumour heterogeneity conserved karyotype, displaying only modest increase mutations, although frequencies structural variants are elevated overall. Furthermore, highly variable tumour-specific contributions mutational footprints endogenous (for example, SBS1 APOBEC) exogenous processes platinum treatment) present. The majority types had either moderate lung adenocarcinoma) or consistent portraits ovarian serous carcinoma) when comparing disease. Breast, prostate, thyroid kidney renal clear cell carcinomas pancreatic neuroendocrine exceptions rule, extensive transformation their landscape advanced stages. Exposure treatment further scars tumour genome introduces evolutionary bottleneck that selects for known therapy-resistant drivers approximately half patients. Our data showcase potential whole-genome identify distinctive features provide valuable resource investigate biological basis resistance therapies.

Language: Английский

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Aneuploidy as a promoter and suppressor of malignant growth

Nature reviews. Cancer, Journal Year: 2021, Volume and Issue: 21(2), P. 89 - 103

Published: Jan. 11, 2021

Language: Английский

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Gene copy-number changes and chromosomal instability induced by aneuploidy confer resistance to chemotherapy

Developmental Cell, Journal Year: 2021, Volume and Issue: 56(17), P. 2440 - 2454.e6

Published: Aug. 4, 2021

Language: Английский

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Clonal fitness inferred from time-series modelling of single-cell cancer genomes

Nature, Journal Year: 2021, Volume and Issue: 595(7868), P. 585 - 590

Published: June 23, 2021

Language: Английский

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Effects of aneuploidy on cell behaviour and function

Nature Reviews Molecular Cell Biology, Journal Year: 2022, Volume and Issue: 23(4), P. 250 - 265

Published: Jan. 5, 2022

Language: Английский

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Nuclear chromosome locations dictate segregation error frequencies

Nature, Journal Year: 2022, Volume and Issue: 607(7919), P. 604 - 609

Published: July 13, 2022

Chromosome segregation errors during cell divisions generate aneuploidies and micronuclei, which can undergo extensive chromosomal rearrangements such as chromothripsis1-5. Selective pressures then shape distinct aneuploidy rearrangement patterns-for example, in cancer6,7-but it is unknown whether initial biases micronucleation exist for particular chromosomes. Using single-cell DNA sequencing8 after an error-prone mitosis untransformed, diploid lines organoids, we show that chromosomes have different error frequencies result non-random landscapes. Isolation sequencing of single micronuclei from these cells showed mis-segregating frequently also preferentially become entrapped micronuclei. A similar bias was found naturally occurring two cancer lines. We find individual correlate with their location the interphase nucleus, this highest peripheral behind spindle poles. Randomization chromosome positions, Cas9-mediated live tracking forced repositioning a greater distance nuclear centre directly increases propensity to mis-segregate. Accordingly, chromothripsis genomes9 early development10 occur more larger chromosomes, are located near periphery. Our findings reveal direct link between micronucleus content, implications our understanding tumour genome evolution origins specific development.

Language: Английский

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Tumor initiation and early tumorigenesis: molecular mechanisms and interventional targets

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: June 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.

Language: Английский

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Deterministic evolution and stringent selection during preneoplasia

Nature, Journal Year: 2023, Volume and Issue: 618(7964), P. 383 - 393

Published: May 31, 2023

Abstract The earliest events during human tumour initiation, although poorly characterized, may hold clues to malignancy detection and prevention 1 . Here we model occult preneoplasia by biallelic inactivation of TP53 , a common early event in gastric cancer, organoids. Causal relationships between this initiating genetic lesion resulting phenotypes were established using experimental evolution multiple clonally derived cultures over 2 years. loss elicited progressive aneuploidy, including copy number alterations structural variants prevalent cancers, with evident preferred orders. Longitudinal single-cell sequencing TP53- deficient organoids similarly indicates progression towards malignant transcriptional programmes. Moreover, high-throughput lineage tracing expressed cellular barcodes demonstrates reproducible dynamics whereby initially rare subclones shared programmes repeatedly attain clonal dominance. This powerful platform for exposes stringent selection, interference marked degree phenotypic convergence premalignant epithelial These data imply predictability the stages tumorigenesis show evolutionary constraints barriers transformation, implications earlier interception aggressive, genome-instable tumours.

Language: Английский

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Short-term molecular consequences of chromosome mis-segregation for genome stability

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: March 11, 2023

Chromosome instability (CIN) is the most common form of genome and a hallmark cancer. CIN invariably leads to aneuploidy, state karyotype imbalance. Here, we show that aneuploidy can also trigger CIN. We found aneuploid cells experience DNA replication stress in their first S-phase precipitate continuous This generates repertoire genetically diverse with structural chromosomal abnormalities either continue proliferating or stop dividing. Cycling display lower complexity compared arrested ones increased expression repair signatures. Interestingly, same signatures are upregulated highly-proliferative cancer cells, which might enable them proliferate despite disadvantage conferred by aneuploidy-induced Altogether, our study reveals short-term origins following indicates as point mutation-independent source instability, providing an explanation for occurrence tumors.

Language: Английский

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

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: March 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.

Language: Английский

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