北京大学白凡、徐涛研究组合作取得最新进展。他们发现形态正常人尿路上皮的宏观体细胞克隆扩增。2020年10月2日出版的《科学》杂志发表了该论文。

在这项研究中，他们研究了形态正常人尿路上皮（MNU；膀胱和输尿管上皮）的体细胞克隆事件，并进行了宏观克隆扩增。马兜铃酸（AA）是一种天然草药来源的化合物，是MNU中的主要诱变驱动因素。AA极大地加速了突变积累并增强了克隆扩增。

在染色质重塑基因（如KMT2D和KDM6A）中广泛观察到MNU突变，但在TP53，PIK3CA和FGFR3中很少见。KMT2D突变在尿道上皮细胞中很常见，无论这些细胞是否接触外源性诱变剂。拷贝数的改变很少见，并且主要局限于小范围的区域，以及拷贝中性的杂合性丧失。MNU中与AA相关的单个克隆扩展到几平方厘米的大小。

据悉，目前仍然缺乏对正常细胞中体细胞突变积累的了解，这对于理解癌症的发生和发展至关重要。

附：英文原文

Title: Macroscopic somatic clonal expansion in morphologically normal human urothelium

Author: Ruoyan Li, Yiqing Du, Zhanghua Chen, Deshu Xu, Tianxin Lin, Shanzhao Jin, Gongwei Wang, Ziyang Liu, Min Lu, Xu Chen, Tao Xu, Fan Bai

Issue&Volume: 2020/10/02

Abstract: Knowledge of somatic mutation accumulation in normal cells, which is essential for understanding cancer development and evolution, remains largely lacking. In this study, we investigated somatic clonal events in morphologically normal human urothelium (MNU; epithelium lining the bladder and ureter) and identified macroscopic clonal expansions. Aristolochic acid (AA), a natural herb-derived compound, was a major mutagenic driving factor in MNU. AA drastically accelerates mutation accumulation and enhances clonal expansion. Mutations in MNU were widely observed in chromatin remodeling genes such as KMT2D and KDM6A but rarely in TP53, PIK3CA, and FGFR3. KMT2D mutations were found to be common in urothelial cells, regardless of whether the cells experience exogenous mutagen exposure. Copy number alterations were rare and largely confined to small-scale regions, along with copy-neutral loss of heterozygosity. Single AA-associated clones in MNU expanded to a scale of several square centimeters in size.

DOI: 10.1126/science.aba7300

Source: https://science.sciencemag.org/content/370/6512/82