Mutational signature analysis predicts bacterial hypermutation and multidrug resistance DOI Creative Commons

Kalen M. Hall,

Leonard G. Williams,

Richard D. Smith

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Jan. 2, 2025

Bacteria of clinical importance, such as Pseudomonas aeruginosa, can become hypermutators upon loss DNA mismatch repair (MMR) and are clinically correlated with high rates multidrug resistance (MDR). Here, we demonstrate that hypermutated MMR-deficient P. aeruginosa has a unique mutational signature rapidly acquires MDR repeated exposure to first-line or last-resort antibiotics. acquisition was irrespective drug class instead arose through common mechanisms shared between the initial secondary drugs. Rational combinations drugs having distinct prevented in aeruginosa. Mutational analysis across different human disease contexts identified appreciable quantities isolates were already prone future acquisition. patient samples is promising diagnostic tool may predict guide precision-based medical care. identifies hypermutator strains prognostically predicts acquisiton, potentially serving effective personalized treatment.

Language: Английский

A pan-cancer analysis of the microbiome in metastatic cancer DOI Creative Commons
Thomas Battaglia,

Iris Mimpen,

Joleen J.H. Traets

et al.

Cell, Journal Year: 2024, Volume and Issue: 187(9), P. 2324 - 2335.e19

Published: April 1, 2024

Microbial communities are resident to multiple niches of the human body and important modulators host immune system responses anticancer therapies. Recent studies have shown that complex microbial present within primary tumors. To investigate presence relevance microbiome in metastases, we integrated mapping assembly-based metagenomics, genomics, transcriptomics, clinical data 4,160 metastatic tumor biopsies. We identified organ-specific tropisms microbes, enrichments anaerobic bacteria hypoxic tumors, associations between diversity tumor-infiltrating neutrophils, association Fusobacterium with resistance checkpoint blockade (ICB) lung cancer. Furthermore, longitudinal sampling revealed temporal evolution depleted upon ICB. Together, generated a pan-cancer resource may contribute advancing treatment strategies.

Language: Английский

Citations

52
Evolutionary histories of breast cancer and related clones DOI Creative Commons
T Nishimura, Nobuyuki Kakiuchi, Kenichi Yoshida

et al.

Nature, Journal Year: 2023, Volume and Issue: 620(7974), P. 607 - 614

Published: July 26, 2023

Recent studies have documented frequent evolution of clones carrying common cancer mutations in apparently normal tissues, which are implicated development1-3. However, our knowledge is still missing with regard to what additional driver events take place order, before one or more these tissues ultimately evolve cancer. Here, using phylogenetic analyses multiple microdissected samples from both and non-cancer lesions, we show unique evolutionary histories breast cancers harbouring der(1;16), a alteration found roughly 20% cancers. The approximate timing early was estimated the mutation rate measured epithelial cells. In der(1;16)(+) cancers, derivative chromosome acquired puberty late adolescence, followed by emergence ancestor patient's 30s, evolved. Replacing pre-existing mammary epithelium following years, occupied large area within premenopausal time diagnosis. Evolution independent founders ancestors common, contributing intratumour heterogeneity. number did not correlate histology, suggesting role local microenvironments and/or epigenetic events. A similar pattern also observed another case evolving an AKT1-mutated founder. Taken together, findings provide new insight into how evolves.

Language: Английский

Citations

48
Assigning mutational signatures to individual samples and individual somatic mutations with SigProfilerAssignment DOI Creative Commons
Marcos Díaz‐Gay, Raviteja Vangara, Mark Barnes

et al.

Bioinformatics, Journal Year: 2023, Volume and Issue: 39(12)

Published: Dec. 1, 2023

Analysis of mutational signatures is a powerful approach for understanding the mutagenic processes that have shaped evolution cancer genome. To evaluate operative in genome, one first needs to quantify their activities by estimating number mutations imprinted each signature.

Language: Английский

Citations

47
Accelerated evolution of SARS-CoV-2 in free-ranging white-tailed deer DOI Creative Commons
Dillon S. McBride, Sofya K. Garushyants,

John Franks

et al.

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

Published: Aug. 28, 2023

Abstract The zoonotic origin of the COVID-19 pandemic virus highlights need to fill vast gaps in our knowledge SARS-CoV-2 ecology and evolution non-human hosts. Here, we detected that was introduced from humans into white-tailed deer more than 30 times Ohio, USA during November 2021-March 2022. Subsequently, deer-to-deer transmission persisted for 2–8 months, disseminating across hundreds kilometers. Newly developed Bayesian phylogenetic methods quantified how is not only three-times faster compared rate observed but also driven by different mutational biases selection pressures. long-term effect this accelerated evolutionary remains be seen as no critical phenotypic changes were animal models using viruses. Still, has transmitted populations a relatively short duration, risk future may have serious consequences livestock.

Language: Английский

Citations

44
Improved detection of colibactin-induced mutations by genotoxic E. coli in organoids and colorectal cancer DOI Creative Commons
Axel K.M. Rosendahl Huber, Cayetano Pleguezuelos‐Manzano, Jens Puschhof

et al.

Cancer Cell, Journal Year: 2024, Volume and Issue: 42(3), P. 487 - 496.e6

Published: March 1, 2024

Co-culture of intestinal organoids with a colibactin-producing pks+ E. coli strain (EcC) revealed mutational signatures also found in colorectal cancer (CRC). Nissle 1917 (EcN) remains commonly used probiotic, despite harboring the pks operon and inducing double strand DNA breaks. We determine mutagenicity EcN three CRC-derived strains an analytical framework based on sequence characteristic colibactin-induced mutations. All strains, including EcN, display varying levels mutagenic activity. Furthermore, machine learning approach attributing individual mutations to colibactin reveals that patients are diagnosed at younger age can induce specific APC mutation. These approaches allow sensitive detection ∼12% CRC genomes even whole exome sequencing data, representing crucial step toward pinpointing activity distinct strains.

Language: Английский

Citations

26
Integrated transcriptome landscape of ALS identifies genome instability linked to TDP-43 pathology DOI Creative Commons
Oliver J. Ziff, Jacob Neeves, Jamie S. Mitchell

et al.

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

Published: April 20, 2023

Abstract Amyotrophic Lateral Sclerosis (ALS) causes motor neuron degeneration, with 97% of cases exhibiting TDP-43 proteinopathy. Elucidating pathomechanisms has been hampered by disease heterogeneity and difficulties accessing neurons. Human induced pluripotent stem cell-derived neurons (iPSMNs) offer a solution; however, studies have typically limited to underpowered cohorts. Here, we present comprehensive compendium 429 iPSMNs from 15 datasets, 271 post-mortem spinal cord samples. Using reproducible bioinformatic workflows, identify robust upregulation p53 signalling in ALS both cord. activation is greatest C9orf72 repeat expansions but weakest SOD1 FUS mutations. depletion potentiates neuronal nuclei cell culture, thereby functionally linking depletion. tissue display enrichment splicing alterations, somatic mutations, gene fusions, possibly contributing the DNA damage response.

Language: Английский

Citations

34
Genomic mutation landscape of skin cancers from DNA repair-deficient xeroderma pigmentosum patients DOI Creative Commons
Andrey A. Yurchenko, Fatemeh Rajabi, Tirzah Braz Petta Lajus

et al.

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

Published: May 4, 2023

Abstract Xeroderma pigmentosum (XP) is a genetic disorder caused by mutations in genes of the Nucleotide Excision Repair (NER) pathway (groups A-G) or Translesion Synthesis DNA polymerase η (V). XP associated with an increased skin cancer risk, reaching, for some groups, several thousand-fold compared to general population. Here, we analyze 38 genomes from five groups. We find that activity NER determines heterogeneity mutation rates across and transcription-coupled extends beyond gene boundaries reducing intergenic rate. Mutational profile XP-V tumors experiments POLH knockout cell line reveal role error-free bypass (i) rare TpG TpA lesions, (ii) 3’ nucleotides pyrimidine dimers, (iii) TpT photodimers. Our study unravels basis risk provides insights into mechanisms UV-induced mutagenesis

Language: Английский

Citations

30
The chemotherapeutic drug CX-5461 is a potent mutagen in cultured human cells DOI Creative Commons
Ching Chiek Koh,

Soraya Boushaki,

Salome Jingchen Zhao

et al.

Nature Genetics, Journal Year: 2023, Volume and Issue: 56(1), P. 23 - 26

Published: Nov. 30, 2023

Abstract The chemotherapeutic agent CX-5461, or pidnarulex, has been fast-tracked by the United States Food and Drug Administration for early-stage clinical studies of BRCA1- , BRCA2- PALB2 -mutated cancers. It is under investigation in phase I II trials. Here, we find that, although CX-5461 exhibits synthetic lethality BRCA1-/BRCA2 -deficient cells, it also causes extensive, nonselective, collateral mutagenesis all three cell lines tested, to magnitudes that exceed known environmental carcinogens.

Language: Английский

Citations

27
Distinguishing preferences of human APOBEC3A and APOBEC3B for cytosines in hairpin loops, and reflection of these preferences in APOBEC-signature cancer genome mutations DOI Creative Commons
Yasha Nazir Butt, Ramin Sakhtemani, Rukshana Mohamad-Ramshan

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: March 18, 2024

Abstract The APOBEC3 enzymes convert cytosines in single-stranded DNA to uracils protect against viruses and retrotransposons but can contribute mutations that diversify tumors. To understand the mechanism of mutagenesis, we map resulting from expression APOBEC3B or its catalytic carboxy-terminal domain (CTD) Escherichia coli . Like APOBEC3A, uracilomes A3B A3B-CTD show a preference deaminate near transcription start sites lagging-strand replication templates hairpin loops. Both biochemical activities genomic uracil distribution A3A prefers 3 nt loops best, while 4 Reanalysis loop human tumors finds intrinsic characteristics both enzymes, with much stronger contribution A3A. We apply Hairpin Signatures 1 2, which define preferences respectively are orthogonal published methods, evaluate their tumor mutations.

Language: Английский

Citations

12
Mesenchymal tumor organoid models recapitulate rhabdomyosarcoma subtypes DOI
Michael T. Meister, Marian J.A. Groot Koerkamp,

Terezinha de Souza

et al.

EMBO Molecular Medicine, Journal Year: 2022, Volume and Issue: 14(10)

Published: Aug. 2, 2022

Language: Английский

Citations

38