Development, maturation, and maintenance of human prostate inferred from somatic mutations

Area of Science:

• Genomics
• Developmental Biology
• Cancer Research

Background:

• Understanding clonal dynamics and mutation burden in normal prostate epithelium is crucial for deciphering prostate cancer development.
• Previous studies have lacked comprehensive analysis of somatic mutations across the lifespan of healthy prostate tissue.

Observation:

• Whole genomes from 409 microdissections of normal prostate epithelium from 8 donors were sequenced.
• Phylogenetic reconstruction and spatial mapping were employed to reconstruct tissue dynamics in a 59-year-old man's prostate.

Findings:

• Somatic mutations accumulate at approximately 16 mutations/year/clone, with higher rates in peripheral regions.
• Prostate glandular subunits form during fetal development, with further branching occurring during puberty.
• Clonal expansions in adult tissue show limited scope and migration; driver mutations are rare but can cause significant expansion.

Implications:

• This study defines prostate stem cell dynamics throughout development and aging using unbiased clock-like mutations.
• Insights into normal tissue dynamics may inform early detection and prevention strategies for prostate cancer.