英国剑桥大学Peter J. Campbell、纽卡斯尔大学Rakesh Heer等研究人员合作绘制人类前列腺中的体细胞突变图谱。相关论文于2021年3月2日在线发表在《细胞—干细胞》杂志上。

研究人员对来自8个捐献者正常前列腺上皮的409个显微解剖样品进行了全基因组测序，并在一名59岁男性的前列腺中进行了系统发育重建和空间映射，从而重建出整个生命周期的组织动力学。体细胞突变以每年约16个突变/年/克隆的速率稳定地累积，其外围区域的发生率高于尿道周围区域。

在胎儿发育过程中，由5-10个胚胎细胞分别建立起24-30个独立的腺亚单位。青春期会通过发育过程中散布的干细胞进一步诱导侧面和末端分支的形成。在成人组织维持期间，克隆扩增具有有限的分布范围和最小的迁移。驱动程序突变在老年的前列腺上皮中很少见，但研究人员确实观察到的一个驱动程序产生了相当大的上皮内克隆扩增。通过无偏的时钟样突变，研究人员定义了胎儿发育、青春期和衰老中的前列腺干细胞动力学。

据悉，健康人类前列腺上皮细胞中的克隆动力学和突变负担与前列腺癌有关。

附：英文原文

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

Author: Sebastian Grossmann, Yvette Hooks, Laura Wilson, Luiza Moore, Laura O’Neill, Iigo Martincorena, Thierry Voet, Michael R. Stratton, Rakesh Heer, Peter J. Campbell

Issue&Volume: 2021-03-02

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.

DOI: 10.1016/j.stem.2021.02.005

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(21)00055-2