Aneuploidy renders cancer cells vulnerable to mitotic checkpoint inhibition

Nature, Journal Year: 2021, Volume and Issue: 590(7846), P. 486 - 491

Published: Jan. 27, 2021

Language: Английский

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A pan-cancer compendium of chromosomal instability

Nature, Journal Year: 2022, Volume and Issue: 606(7916), P. 976 - 983

Published: June 15, 2022

Language: Английский

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Meningioma DNA methylation groups identify biological drivers and therapeutic vulnerabilities

Nature Genetics, Journal Year: 2022, Volume and Issue: 54(5), P. 649 - 659

Published: May 1, 2022

Language: Английский

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Deep whole-genome ctDNA chronology of treatment-resistant prostate cancer

Nature, Journal Year: 2022, Volume and Issue: 608(7921), P. 199 - 208

Published: July 20, 2022

Language: Английский

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Oncogene-like addiction to aneuploidy in human cancers

Science, Journal Year: 2023, Volume and Issue: 381(6660)

Published: July 6, 2023

Most cancers exhibit aneuploidy, but its functional significance in tumor development is controversial. Here, we describe ReDACT (Restoring Disomy Aneuploid cells using CRISPR Targeting), a set of chromosome engineering tools that allow us to eliminate specific aneuploidies from cancer genomes. Using ReDACT, created panel isogenic have or lack common aneuploidies, and demonstrate trisomy 1q required for malignant growth harboring this alteration. Mechanistically, gaining increases the expression

Language: Английский

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Cyclin E-induced replicative stress drives p53-dependent whole-genome duplication

Cell, Journal Year: 2023, Volume and Issue: 186(3), P. 528 - 542.e14

Published: Jan. 20, 2023

Whole-genome duplication (WGD) is a frequent event in cancer evolution and an important driver of aneuploidy. The role the p53 tumor suppressor WGD has been enigmatic: can block proliferation tetraploid cells, acting as barrier to WGD, but also promote mitotic bypass, key step via endoreduplication. In wild-type (WT) tumors, frequently associated with activation E2F pathway, especially amplification CCNE1, encoding cyclin E1. Here, we show that elevated E1 expression causes replicative stress, which activates ATR- Chk1-dependent G2 phase arrest. p53, its downstream target p21, together Wee1, then inhibits cyclin-dependent kinase activity sufficiently activate APC/CCdh1 bypass. Cyclin E suppresses p53-dependent senescence after allowing cells complete Our results indicate contribute through promotion WGD.

Language: Английский

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MEDICC2: whole-genome doubling aware copy-number phylogenies for cancer evolution

Genome biology, Journal Year: 2022, Volume and Issue: 23(1)

Published: Nov. 14, 2022

Abstract Aneuploidy, chromosomal instability, somatic copy-number alterations, and whole-genome doubling (WGD) play key roles in cancer evolution provide information for the complex task of phylogenetic inference. We present MEDICC2, a method inferring evolutionary trees WGD using haplotype-specific alterations from single-cell or bulk data. MEDICC2 eschews simplifications such as infinite sites assumption, allowing multiple mutations parallel evolution, does not treat adjacent loci independent, overlapping events. Using simulations data types 2780 tumors, we use to demonstrate accurate inference phylogenies, clonal subclonal WGD, ancestral states.

Language: Английский

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Evolutionary history of transformation from chronic lymphocytic leukemia to Richter syndrome

Nature Medicine, Journal Year: 2023, Volume and Issue: 29(1), P. 158 - 169

Published: Jan. 1, 2023

Language: Английский

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Multiomic analysis of malignant pleural mesothelioma identifies molecular axes and specialized tumor profiles driving intertumor heterogeneity

Nature Genetics, Journal Year: 2023, Volume and Issue: 55(4), P. 607 - 618

Published: March 16, 2023

Abstract Malignant pleural mesothelioma (MPM) is an aggressive cancer with rising incidence and challenging clinical management. Through a large series of whole-genome sequencing data, integrated transcriptomic epigenomic data using multiomics factor analysis, we demonstrate that the current World Health Organization classification only accounts for up to 10% interpatient molecular differences. Instead, MESOMICS project paves way morphomolecular MPM based on four dimensions: ploidy, tumor cell morphology, adaptive immune response CpG island methylator profile. We show these dimensions are complementary, capture major differences delimited by extreme phenotypes that—in case interdependent morphology adapted response—reflect specialization. These findings unearth interplay between functional biology its genomic history, provide insights into variations observed in behavior patients MPM.

Language: Английский

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Multiomic analysis of homologous recombination-deficient end-stage high-grade serous ovarian cancer

Nature Genetics, Journal Year: 2023, Volume and Issue: 55(3), P. 437 - 450

Published: Feb. 27, 2023

Language: Английский

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