Development, Maturation, and Maintenance of Human Prostate Inferred from Somatic Mutations

Overview

Journal Cell Stem Cell

Publisher Cell Press

Specialty Cell Biology

Date 2021 Mar 3

PMID 33657416

Citations 17

Authors

Sebastian Grossmann

Yvette Hooks

Laura Wilson

Luiza Moore

Laura ONeill

Inigo Martincorena

Thierry Voet

Michael R Stratton

Rakesh Heer

Peter J Campbell

Affiliations

Soon will be listed here.

Abstract

Clonal dynamics and mutation burden in healthy human prostate epithelium are relevant to prostate cancer. We sequenced whole genomes from 409 microdissections of normal prostate epithelium across 8 donors, using phylogenetic reconstruction with spatial mapping in a 59-year-old man's prostate to reconstruct tissue dynamics across the lifespan. Somatic mutations accumulate steadily at ∼16 mutations/year/clone, with higher rates in peripheral than peri-urethral regions. The 24-30 independent glandular subunits are established as rudimentary ductal structures during fetal development by 5-10 embryonic cells each. Puberty induces formation of further side and terminal branches by local stem cells disseminated throughout the rudimentary ducts during development. During adult tissue maintenance, clonal expansions have limited geographic scope and minimal migration. Driver mutations are rare in aging prostate epithelium, but the one driver we did observe generated a sizable intraepithelial clonal expansion. Leveraging unbiased clock-like mutations, we define prostate stem cell dynamics through fetal development, puberty, and aging.

Citing Articles

Prolonged persistence of mutagenic DNA lesions in somatic cells.

Spencer Chapman M, Mitchell E, Yoshida K, Williams N, Fabre M, Ranzoni A Nature. 2025; 638(8051):729-738.

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Clonal expansion in normal tissues.

Maeda H, Kakiuchi N Cancer Sci. 2024; 115(7):2117-2124.

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Somatic mutations in aging and disease.

Ren P, Zhang J, Vijg J Geroscience. 2024; 46(5):5171-5189.

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Spatial architectures of somatic mutations in normal prostate, benign prostatic hyperplasia and coexisting prostate cancer.

Chae J, Jung S, Choi E, Kim J, Kim N, Moon S Exp Mol Med. 2024; 56(1):168-176.

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Commonalities and differences in the mutational signature and somatic driver mutation landscape across solid and hollow viscus organs.

Ng A, Chan D Oncogene. 2023; 42(37):2713-2724.

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