Abstract：
Recent research on normal human tissues identified omnipresent clones of cells, driven by somatic mutations known to be responsible for carcinogenesis (e.g., in TP53 or NOTCH1). These new insights are fundamentally changing current tumor evolution models, with broad oncological implications. Most studies are based on surgical remnant tissues, which are not available for many organs and rarely in a pan-organ setting (multiple organs from the same individual). Here, we describe an approach based on clinically annotated post-mortem tissues, derived from whole-body donors that are routinely used for educational purposes at human anatomy units. We validated this post-mortem approach using UV-exposed and unexposed epidermal skin tissues and confirm the presence of positively selected NOTCH1/2-, TP53- and FAT1-driven clones. No selection signals were detected in a set of immune genes or housekeeping genes. Additionally, we provide the first evidence for smoking-induced clonal changes in oral epithelia, likely underlying the origin of head and neck carcinogenesis. In conclusion, the whole-body donor-based approach provides a nearly unlimited healthy tissue resource to study mutational clonality and gain fundamental mutagenic insights in the presumed earliest stages of tumor evolution.
摘要：
最近对正常人组织的研究发现了无所不在的细胞克隆，由已知负责致癌作用的体细胞突变驱动(例如，在TP53或NOTCH1中)。这些新见解正在从根本上改变当前的肿瘤进化模型，具有广泛的肿瘤学意义。大多数研究是基于手术残余组织，它不适用于许多器官，很少在泛器官环境中（来自同一个人的多个器官）。这里,我们描述了一种基于临床注释的尸检组织的方法，来源于全身捐赠者，通常用于人体解剖学单位的教育目的。我们使用紫外线暴露和未暴露的表皮皮肤组织验证了这种验尸方法，并确认了阳性选择的NOTCH1/2-，TP53-和FAT1驱动的克隆。在一组免疫基因或管家基因中未检测到选择信号。此外,我们提供了吸烟引起的口腔上皮克隆变化的第一个证据，可能是头颈部癌变的起源。总之,基于全身供体的方法为研究突变克隆性提供了几乎无限的健康组织资源，并在假定的肿瘤进化的最早阶段获得了基本的诱变见解。
