Extensive heterogeneity in somatic mutation and selection in the human bladder

Lawson, Andrew; Abascal, Federico; Coorens, Tim; Hooks, Yvette; O’Neill, Laura P.; Latimer, Calli; Raine, Keiran; Sanders, Mathijs A.; Warren, Anne Y.; Mahbubani, Krishnaa T.; Bareham, Bethany Kate; Butler, Timothy; Harvey, Luke M. R.; Cagan, Alex; Menzies, Andrew; Moore, Luiza; Colquhoun, Alexandra; Turner, William H.; Thomas, Benjamin; Gnanapragasam, Vincent; Williams, Nicholas; Rassl, Doris M.; Vöhringer, Harald; Zumalave, Sonia; Nangalia, Jyoti; Tubío, José M. C.; Gerstung, Moritz; Saeb‐Parsy, Kourosh; Stratton, Michael R.; Campbell, Peter J.; Mitchell, Thomas J.; Martincorena, Iñigo

doi:10.1126/science.aba8347

Cited by 213 publications

(179 citation statements)

References 73 publications

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“…Compared to somatic mutations, CNAs are relatively rare and less extensive in the normal tissues from different organs, consistent with previous analyses 5,6,14,15 . In our study, liver samples harbored high mutational burdens coupled with obvious clonal expansions, however, CNAs were seldomly seen across the entire genome.…”

Section: Discussionsupporting

confidence: 91%

“…Recent studies have revealed the somatic mutation landscape of different normal human tissues, including the skin 3,4 , esophagus 5,6 , colon and rectum 7 , liver 8 , endometrial epithelium 9 , bronchia 10 , brain 11,12 , embryo 13 , urothelium 14,15 , and blood cells 16,17 , mostly through deep DNA sequencing of biopsied tissue samples. Other studies have implemented bioinformatic algorithms to detect somatic mutations from RNA sequencing data of normal human tissues 18,19 .…”

Section: Introductionmentioning

confidence: 99%

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A body map of somatic mutagenesis in morphologically normal human tissues

Lin

et al. 2020

Preprint

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Somatic mutations accumulated in normal tissues are associated with aging and disease. Here, we performed a comprehensive genomic analysis of 1,737 morphologically normal tissue biopsies (~ 600 cells each), mostly from the epithelia, of nine organs from five donors. We found that somatic mutation accumulations and clonal expansions are widespread, although with variable extent, in morphologically normal human tissues. Somatic copy number alterations were rarely detected, except for tissues from esophagus and cardia. Endogenous mutational processes like SBS1 and SBS5 are ubiquitous among normal tissues though exhibiting different relative activities. Exogenous mutational processes like SBS22 were found in different tissues from the same donor. We reconstructed the spatial somatic clonal architecture with sub-millimeter resolution. In epithelial tissues from esophagus and cardia, macroscopic somatic clones expanded to several millimeters were frequently seen, whereas in tissues from colon, rectum, and duodenum somatic clones were microscopic in size and evolved independently. Our study depicted a body map of somatic mutations and clonal expansions from the same individuals, and it revealed that the degree of somatic clonal expansion and enrichment of driver mutations are highly organ specific.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

A body map of somatic mutagenesis in morphologically normal human tissues

Lin

et al. 2020

Preprint

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“…Using multiple samples from the same individuals, we have compared clonal structures, mutation rates and mutational signatures across an extensive range of normal cell types, substantially extending results from previous studies 2,9–11,13,45,46 . Our results revealed the extent of variation in clonal dynamics across tissues.…”

Section: Discussionmentioning

confidence: 60%

“…Patches of cells dissected from seminiferous tubules of the testis were frequently monoclonal, indicating that they arise from single spermatogonial stem cells. The mutation burdens of these germ cell clones were ~27 fold lower than colorectal crypts from the same individuals and their mutation burdens accumulated with age in a linear manner at 2.02 mutations/year (CI95% 1.83-2.42), lower than all other somatic cells thus far estimated 2,9–11,13,45,46 . How the male germline achieves this low mutation rate has remained elusive.…”

Section: Discussionmentioning

confidence: 84%

The mutational landscape of human somatic and germline cells

Moore

Cagan

Coorens

et al. 2020

Preprint

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During the course of a lifetime normal human cells accumulate mutations. Here, using multiple samples from the same individuals we compared the mutational landscape in 29 anatomical structures from soma and the germline. Two ubiquitous mutational signatures, SBS1 and SBS5/40, accounted for the majority of acquired mutations in most cell types but their absolute and relative contributions varied substantially. SBS18, potentially reflecting oxidative damage, and several additional signatures attributed to exogenous and endogenous exposures contributed mutations to subsets of cell types. The mutation rate was lowest in spermatogonia, the stem cell from which sperm are generated and from which most genetic variation in the human population is thought to originate. This was due to low rates of ubiquitous mutation processes and may be partially attributable to a low cell division rate of basal spermatogonia. The results provide important insights into how mutational processes affect the soma and germline.

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“…It should be noted that SigProfilerExtractor provides extensive output for the interrogated total (vi) to exome downsampling of all 88 whole-genome sequenced microbiopsies of histologically normal urothelium 33 . In all cases, the mutational catalogues of each samples were taken from the respective original publications.…”

Section: Module 7: Outputting and Plotting Of Analysis Resultsmentioning

confidence: 99%

Uncovering novel mutational signatures by de novo extraction with SigProfilerExtractor

Islam

Díaz‐Gay

et al. 2020

Preprint

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Mutational signature analysis is commonly performed in genomic studies surveying cancer and normal somatic tissues. Here we present SigProfilerExtractor, an automated tool for accurate de novo extraction of mutational signatures for all types of somatic mutations. Benchmarking with a total of 33 distinct scenarios encompassing 1,106 simulated signatures operative in more than 200,000 synthetic genomes demonstrates that SigProfilerExtractor outperforms ten other tools across all datasets with and without noise. For simulations with 5% noise, reflecting high-quality genomic datasets, SigProfilerExtractor outperforms other approaches by elucidating between 20% and 50% more true positive signatures while yielding more than 5-fold less false positive signatures. Applying SigProfilerExtractor to 2,778 whole-genome sequenced cancers reveals three previously missed mutational signatures. Two of the signatures are confirmed in independent cohorts with one of these signatures associating with tobacco smoking. In summary, this report provides a reference tool for analysis of mutational signatures, a comprehensive benchmarking of bioinformatics tools for extracting mutational signatures, and several novel mutational signatures including a signature putatively attributed to direct tobacco smoking mutagenesis in bladder cancer and in normal bladder epithelium.

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Extensive heterogeneity in somatic mutation and selection in the human bladder

Cited by 213 publications

References 73 publications

A body map of somatic mutagenesis in morphologically normal human tissues

A body map of somatic mutagenesis in morphologically normal human tissues

The mutational landscape of human somatic and germline cells

Uncovering novel mutational signatures by de novo extraction with SigProfilerExtractor

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