Genome-wide mapping of somatic mutation rates uncovers drivers of cancer DOI Creative Commons
Maxwell A. Sherman, Adam Yaari,

Oliver Priebe

et al.

Nature Biotechnology, Journal Year: 2022, Volume and Issue: 40(11), P. 1634 - 1643

Published: June 20, 2022

Abstract Identification of cancer driver mutations that confer a proliferative advantage is central to understanding cancer; however, searches have often been limited protein-coding sequences and specific non-coding elements (for example, promoters) because the challenge modeling highly variable somatic mutation rates observed across tumor genomes. Here we present Dig, method search for anywhere in genome. We use deep neural networks map cancer-specific genome-wide at kilobase-scale resolution. These estimates are then refined evidence under positive selection throughout genome by comparing expected counts. mapped 37 types applied these maps identify putative drivers within intronic cryptic splice regions, 5′ untranslated regions infrequently mutated genes. Our high-resolution rate maps, available web-based exploration, resource enable discovery genome-wide.

Language: Английский

Somatic mutation rates scale with lifespan across mammals DOI Creative Commons
Alex Cagan, Adrian Baez‐Ortega, Natalia Brzozowska

et al.

Nature, Journal Year: 2022, Volume and Issue: 604(7906), P. 517 - 524

Published: April 13, 2022

Abstract The rates and patterns of somatic mutation in normal tissues are largely unknown outside humans 1–7 . Comparative analyses can shed light on the diversity mutagenesis across species, long-standing hypotheses about evolution their role cancer ageing. Here we performed whole-genome sequencing 208 intestinal crypts from 56 individuals to study landscape 16 mammalian species. We found that was dominated by seemingly endogenous mutational processes all including 5-methylcytosine deamination oxidative damage. With some differences, signatures other species resembled those described 8 , although relative contribution each signature varied Notably, rate per year greatly exhibited a strong inverse relationship with lifespan, no life-history trait studied showing comparable association. Despite widely different life histories among examined—including variation around 30-fold lifespan 40,000-fold body mass—the burden at end only factor 3. These data unveil common mammals, suggest evolutionarily constrained may be contributing

Language: Английский

Citations

335
Mutation bias reflects natural selection in Arabidopsis thaliana DOI Creative Commons
J. Grey Monroe, Thanvi Srikant, Pablo Carbonell‐Bejerano

et al.

Nature, Journal Year: 2022, Volume and Issue: 602(7895), P. 101 - 105

Published: Jan. 12, 2022

Abstract Since the first half of twentieth century, evolutionary theory has been dominated by idea that mutations occur randomly with respect to their consequences 1 . Here we test this assumption large surveys de novo in plant Arabidopsis thaliana In contrast expectations, find less often functionally constrained regions genome—mutation frequency is reduced inside gene bodies and two-thirds essential genes. With independent genomic mutation datasets, including from largest accumulation experiment conducted date, demonstrate epigenomic physical features explain over 90% variance genome-wide pattern bias surrounding Observed frequencies around genes turn accurately predict patterns genetic polymorphisms natural accessions ( r = 0.96). That primary force behind sequence evolution supported analyses allele frequencies. Finally, subject stronger purifying selection have a lower rate. We conclude epigenome-associated 2 reduces occurrence deleterious , challenging prevailing paradigm directionless evolution.

Language: Английский

Citations

317
Mechanisms of APOBEC3 mutagenesis in human cancer cells DOI Creative Commons
Mia Petljak, Alexandra Dananberg, Kevan Chu

et al.

Nature, Journal Year: 2022, Volume and Issue: 607(7920), P. 799 - 807

Published: July 20, 2022

The APOBEC3 family of cytosine deaminases has been implicated in some the most prevalent mutational signatures cancer1-3. However, a causal link between endogenous enzymes and human cancer genomes not established, leaving mechanisms mutagenesis poorly understood. Here, to investigate mutagenesis, we deleted genes from cell lines that naturally generate APOBEC3-associated over time4. Analysis non-clustered clustered across whole-genome sequences 251 breast, bladder lymphoma line clones revealed APOBEC3A deletion diminished signatures. Deletion both APOBEC3B further decreased mutation burdens, without eliminating them. increased protein levels, activity APOBEC3A-mediated lines. uracil glycosylase UNG was required for APOBEC3-mediated transversions, whereas loss translesion polymerase REV1 overall burdens. Together, these data represent direct evidence cells. Our results identify as main driver mutations, indicate can restrain APOBEC3A-dependent while contributing its own smaller burdens dissect translate activities into distinct

Language: Английский

Citations

185
Pan-cancer whole-genome comparison of primary and metastatic solid tumours DOI Creative Commons
Francisco Martínez-Jiménez, Ali Movasati,

Sascha R. Brunner

et al.

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

Citations

155
A body map of somatic mutagenesis in morphologically normal human tissues DOI
Ruoyan Li,

Lin Di,

Jie Li

et al.

Nature, Journal Year: 2021, Volume and Issue: 597(7876), P. 398 - 403

Published: Aug. 25, 2021

Language: Английский

Citations

149
Cell-free DNA analysis in current cancer clinical trials: a review DOI Creative Commons
Mireya Cisneros-Villanueva, Lizbett Hidalgo Pérez, M. Rios-Romero

et al.

British Journal of Cancer, Journal Year: 2022, Volume and Issue: 126(3), P. 391 - 400

Published: Jan. 13, 2022

Abstract Cell-free DNA (cfDNA) analysis represents a promising method for the diagnosis, treatment selection and clinical follow-up of cancer patients. Although its general methodological feasibility usefulness has been demonstrated, several issues related to standardisation technical validation must be addressed routine application in cancer. In this regard, most cfDNA applications are still limited trials, proving value settings. paper, we review current trials involving cfDNA/ctDNA highlight those where it useful patient stratification, or development novel approaches early diagnosis. Our query included including terms ‘cfDNA’, ‘ctDNA’, ‘liquid biopsy’ AND ‘cancer OR neoplasm’ FDA EMA public databases. We identified 1370 (FDA = 1129, 241) liquid-biopsy These show results detection confirm as tool real-time monitoring acquired therapy resistance, accurate disease-progression surveillance improvement treatment, situations that result better quality life extended overall survival

Language: Английский

Citations

140
Extensive phylogenies of human development inferred from somatic mutations DOI Creative Commons
Tim H. H. Coorens, Luiza Moore, Philip S. Robinson

et al.

Nature, Journal Year: 2021, Volume and Issue: 597(7876), P. 387 - 392

Published: Aug. 25, 2021

Starting from the zygote, all cells in human body continuously acquire mutations. Mutations shared between different imply a common progenitor and are thus naturally occurring markers for lineage tracing1,2. Here we reconstruct extensive phylogenies of normal tissues three adult individuals using whole-genome sequencing 511 laser capture microdissections. Reconstructed embryonic progenitors same generation phylogeny often contribute to extents body. The degree this asymmetry varies individuals, with ratios two reconstructed daughter zygote ranging 60:40 93:7. Asymmetries pervade subsequent generations can differ individual. resolve spatial patterning tissues, revealing contiguous patches of, on average, 301 crypts colonic epithelium derived most recent cell also effect brain development. Using data ten additional men, investigated developmental split soma germline, results suggesting an extraembryonic contribution primordial germ cells. This research demonstrates that, despite reaching ultimate tissue patterns, early bottlenecks commitments lead substantial variation patterns both within individuals. Somatic mutations obtained microdissected biopsies used these back zygote.

Language: Английский

Citations

130
Spatial biology of cancer evolution DOI
Zaira Seferbekova, Artem Lomakin, Lucy Yates

et al.

Nature Reviews Genetics, Journal Year: 2022, Volume and Issue: 24(5), P. 295 - 313

Published: Dec. 9, 2022

Language: Английский

Citations

121
Clonal dynamics in early human embryogenesis inferred from somatic mutation DOI
Seongyeol Park, Nanda Maya Mali, Ryul Kim

et al.

Nature, Journal Year: 2021, Volume and Issue: 597(7876), P. 393 - 397

Published: Aug. 25, 2021

Language: Английский

Citations

113
High-throughput single-сell sequencing in cancer research DOI Creative Commons
Qingzhu Jia, Han Chu, Jin Zheng

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: May 3, 2022

Abstract With advances in sequencing and instrument technology, bioinformatics analysis is being applied to batches of massive cells at single-cell resolution. High-throughput can be utilized for multi-omics characterization tumor cells, stromal or infiltrated immune evaluate progression, responses environmental perturbations, heterogeneous composition the microenvironment, complex intercellular interactions between these factors. Particularly, T cell receptors, alone combination with RNA sequencing, useful fields immunology immunotherapy. Clinical insights obtained from are critically important exploring biomarkers disease progression antitumor treatment, as well guiding precise clinical decision-making patients malignant tumors. In this review, we summarize applications evolution, immunology, Additionally, analyze response heterogeneity resistance checkpoint The limitations cancer research also discussed.

Language: Английский

Citations

104