Single-cell sequencing data reveal widespread recurrence and loss of mutational hits in the life histories of tumors

Genome Research, Journal Year: 2017, Volume and Issue: 27(11), P. 1885 - 1894

Published: Oct. 13, 2017

Intra-tumor heterogeneity poses substantial challenges for cancer treatment. A tumor's composition can be deduced by reconstructing its mutational history. Central to current approaches is the infinite sites assumption that every genomic position only mutate once over lifetime of a tumor. The validity this has never been quantitatively assessed. We developed rigorous statistical framework test with single-cell sequencing data. Our accounts high noise and contamination present in such found strong evidence same being mutationally affected multiple times individual tumors 11 12 data sets from variety human cancers. Seven cases involved loss earlier mutations, five which occurred at unaffected large-scale deletions. Four exhibited parallel mutation, potentially indicating convergent evolution base pair level. results refute general indicate more complex models are needed adequately quantify intra-tumor effective

Language: Английский

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Single-cell multi-omics identifies chronic inflammation as a driver of TP53-mutant leukemic evolution

Nature Genetics, Journal Year: 2023, Volume and Issue: 55(9), P. 1531 - 1541

Published: Sept. 1, 2023

Abstract Understanding the genetic and nongenetic determinants of tumor protein 53 ( TP53 ) - mutation-driven clonal evolution subsequent transformation is a crucial step toward design rational therapeutic strategies. Here we carry out allelic resolution single-cell multi-omic analysis hematopoietic stem/progenitor cells (HSPCs) from patients with myeloproliferative neoplasm who transform to TP53- mutant secondary acute myeloid leukemia (sAML). All showed dominant ‘multihit’ HSPC clones at transformation, stem cell transcriptional signature strongly predictive adverse outcomes in independent cohorts, across both wild-type (WT) AML. Through serial samples, antecedent -heterozygous vivo perturbations, demonstrate hitherto unrecognized effect chronic inflammation, which suppressed WT HSPCs while enhancing fitness advantage promoted evolution. Our findings will facilitate development risk-stratification, early detection treatment strategies for -mutant leukemia, are broad relevance other cancer types.

Language: Английский

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Tumor heterogeneity: preclinical models, emerging technologies, and future applications

Frontiers in Oncology, Journal Year: 2023, Volume and Issue: 13

Published: April 28, 2023

Heterogeneity describes the differences among cancer cells within and between tumors. It refers to describing variations in morphology, transcriptional profiles, metabolism, metastatic potential. More recently, field has included characterization of tumor immune microenvironment depiction dynamics underlying cellular interactions promoting ecosystem evolution. been found most tumors representing one challenging behaviors ecosystems. As critical factors impairing long-term efficacy solid therapy, heterogeneity leads resistance, more aggressive metastasizing, recurrence. We review role main models emerging single-cell spatial genomic technologies our understanding heterogeneity, its contribution lethal outcomes, physiological challenges consider designing therapies. highlight how dynamically evolve because leverage this unleash recognition through immunotherapy. A multidisciplinary approach grounded novel bioinformatic computational tools will allow reaching integrated, multilayered knowledge required implement personalized, efficient therapies urgently for patients.

Language: Английский

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Clonally resolved single-cell multi-omics identifies routes of cellular differentiation in acute myeloid leukemia

Cell stem cell, Journal Year: 2023, Volume and Issue: 30(5), P. 706 - 721.e8

Published: April 24, 2023

Inter-patient variability and the similarity of healthy leukemic stem cells (LSCs) have impeded characterization LSCs in acute myeloid leukemia (AML) their differentiation landscape. Here, we introduce CloneTracer, a novel method that adds clonal resolution to single-cell RNA-seq datasets. Applied samples from 19 AML patients, CloneTracer revealed routes differentiation. Although residual preleukemic dominated dormant cell compartment, active resembled counterpart retained erythroid capacity. By contrast, downstream progenitors constituted highly aberrant, disease-defining compartment: gene expression state affected both chemotherapy response leukemia's ability differentiate into transcriptomically normal monocytes. Finally, demonstrated potential identify surface markers misregulated specifically cells. Taken together, reveals landscape mimics its may determine biology therapy AML.

Language: Английский

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Selective advantage of mutant stem cells in human clonal hematopoiesis is associated with attenuated response to inflammation and aging

Cell stem cell, Journal Year: 2024, Volume and Issue: 31(8), P. 1127 - 1144.e17

Published: June 24, 2024

Clonal hematopoiesis (CH) arises when hematopoietic stem cells (HSCs) acquire mutations, most frequently in the DNMT3A and TET2 genes, conferring a competitive advantage through mechanisms that remain unclear. To gain insight into how CH mutations enable gradual clonal expansion, we used single-cell multi-omics with high-fidelity genotyping on human bone marrow (BM) samples. Most of selective mutant occurs within HSCs. DNMT3A- TET2-mutant clones expand further early progenitors, while accelerate myeloid maturation dose-dependent manner. Unexpectedly, both non-mutant HSCs from samples are enriched for inflammatory aging transcriptomic signatures, compared non-CH samples, revealing non-cell-autonomous effect. However, have an attenuated response relative to wild-type same sample. Our data support model whereby gradually selected because they resistant deleterious impact inflammation aging.

Language: Английский

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Prolonged persistence of mutagenic DNA lesions in somatic cells

Nature, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 15, 2025

Abstract DNA is subject to continual damage, leaving each cell with thousands of individual lesions at any given moment 1–3 . The efficiency repair means that most known classes lesion have a half-life minutes hours 3,4 , but the extent which damage can persist for longer durations remains unknown. Here, using high-resolution phylogenetic trees from 89 donors, we identified mutations arising 818 persisted across multiple cycles in normal human stem cells blood, liver and bronchial epithelium 5–12 Persistent occurred increased rates, distinctive mutational signatures, donors exposed tobacco or chemotherapy, suggesting they arise exogenous mutagens. In haematopoietic cells, persistent lesions, probably endogenous sources, generated characteristic signature SBS19 13 ; steadily throughout life, including utero; endured 2.2 years on average, 15–25% lasting least 3 years. We estimate has approximately eight such time, half will generate mutation cycle. Overall, 16% blood are attributable SBS19, similar proportions driver cancers exhibit this signature. These data indicate existence family mutagens, present low numbers per genome, months years, substantial fraction burden somatic cells.

Language: Английский

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SiFit: inferring tumor trees from single-cell sequencing data under finite-sites models

Genome biology, Journal Year: 2017, Volume and Issue: 18(1)

Published: Sept. 19, 2017

Single-cell sequencing enables the inference of tumor phylogenies that provide insights on intra-tumor heterogeneity and evolutionary trajectories. Recently introduced methods perform this task under infinite-sites assumption, violations which, due to chromosomal deletions loss heterozygosity, necessitate development utilize finite-sites models. We propose a statistical method for from noisy single-cell data model. The performance our synthetic experimental sets two colorectal cancer patients trace lineages in primary metastatic tumors suggests employing model leads improved phylogenies.

Language: Английский

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Advances in understanding tumour evolution through single-cell sequencing

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Journal Year: 2017, Volume and Issue: 1867(2), P. 127 - 138

Published: Feb. 11, 2017

The mutational heterogeneity observed within tumours poses additional challenges to the development of effective cancer treatments. A thorough understanding a tumour's subclonal composition and its history is essential open up design treatments tailored individual patients. Comparative studies on large number permit identification patterns which may refine forecasts progression, response treatment metastatic potential. shaped by evolutionary processes. Recent advances in next-generation sequencing offer possibility analyse accompanying at an unprecedented resolution, single cells. New computational arise when moving from bulk single-cell data, leading novel modelling frameworks. In this review, we present state art methods for phylogeny encoded or highlight future directions developing more comprehensive informative pictures tumour evolution. This article part Special Issue entitled: Evolutionary principles - cancer?, edited Dr. Robert A. Gatenby.

Language: Английский

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Principles of Reconstructing the Subclonal Architecture of Cancers

Cold Spring Harbor Perspectives in Medicine, Journal Year: 2017, Volume and Issue: 7(8), P. a026625 - a026625

Published: March 7, 2017

Most cancers evolve from a single founder cell through series of clonal expansions that are driven by somatic mutations. These can lead to several coexisting subclones sharing subsets Analysis massively parallel sequencing data infer tumor's subclonal composition the identification populations cells with shared We describe principles underlie reconstruction nucleotide variants (SNVs) or copy number alterations (CNAs) bulk single-cell sequencing. include estimating fraction tumor for SNVs and CNAs, performing clustering single- multisample cases, The application methods is providing key insights into evolution, identifying driver mutations, patterns evolution differences in mutational signatures between cellular populations, characterizing mechanisms therapy resistance, spread, metastasis.

Language: Английский

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Integrative inference of subclonal tumour evolution from single-cell and bulk sequencing data

Nature Communications, Journal Year: 2019, Volume and Issue: 10(1)

Published: June 21, 2019

Abstract Understanding the clonal architecture and evolutionary history of a tumour poses one key challenges to overcome treatment failure due resistant cell populations. Previously, studies on subclonal evolution have been primarily based bulk sequencing in some recent cases single-cell data. Either data type alone has shortcomings with regard this task, but methods integrating both types lacking. Here, we present B-SCITE, first computational approach that infers phylogenies from combined Using comprehensive set simulated data, show B-SCITE systematically outperforms existing respect tree reconstruction accuracy subclone identification. provides high-fidelity reconstructions even modest number single cells where allele frequencies are affected by copy changes. On real generated mutation histories high concordance expert trees.

Language: Английский

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