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EGAS00001003049-2-sc-2020-11-16T15:04:08Z - samples

ABSTRACT: Stem cells within prostate epitheliumÃ‚Â frequently undergo malignant transformation, but there is limited informationÃ‚Â on their clonal dynamics and mutation burden inÃ‚Â healthy human prostates. WeÃ‚Â sequenced whole genomes from 409 microdissections of prostate epithelium acrossÃ‚Â 8 donors, using phylogenetic reconstructionÃ‚Â with spatial mapping in aÃ‚Â 59-year-old manÃ¢Â€Â™s prostate to provide high-resolution reconstruction of tissueÃ‚Â dynamics across the lifespan. Somatic mutation burdenÃ‚Â increases linearly withÃ‚Â age, at ~16 mutations/year/clone, and is higher in peripheral thanÃ‚Â peri-urethral regions. The 24-30 independent glandular subunits areÃ‚Â establishedÃ‚Â as rudimentary ductal structures during fetal development by 5-10 embryonicÃ‚Â cells each. Puberty induces formation of further side branches andÃ‚Â terminalÃ‚Â acini by local stem cells disseminated through the rudimentary ducts duringÃ‚Â development. During adult tissue maintenance, clonal expansions are small,Ã‚Â withÃ‚Â limited geographic scope and minimal migration. Driver mutations are rare inÃ‚Â normal ageing prostate epithelium, but the one canonical driver we did observeÃ‚Â generated a sizable intraepithelial clonal expansion. By resolving unbiased,Ã‚Â continuously occurring lineage-marking mutations, we define stem cell dynamicsÃ‚Â through embryogenesis, puberty and ageing, with relevance for prostate cancer.

PROVIDER: EGAD00001006591 | EGA |

REPOSITORIES: EGA

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