Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
MRC Cancer Unit, University of Cambridge, Hutchison-MRC Research Centre, Box 197, Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK.
J R Soc Interface. 2019 Jul 26;16(156):20190230. doi: 10.1098/rsif.2019.0230. Epub 2019 Jul 31.
Cancer develops from mutated cells in normal tissues. Whether somatic mutations alter normal cell dynamics is key to understanding cancer risk and guiding interventions to reduce it. An analysis of the first incomplete moment of size distributions of clones carrying cancer-associated mutations in normal human eyelid skin gives a good fit with neutral drift, arguing mutations do not affect cell fate. However, this suggestion conflicts with genetic evidence in the same dataset that argues for strong positive selection of a subset of mutations. This implies cells carrying these mutations have a competitive advantage over normal cells, leading to large clonal expansions within the tissue. In the normal epithelium, clone growth is constrained by the limited size of the proliferating compartment and competition with surrounding cells. We show that if these factors are taken into account, the first incomplete moment of the clone size distribution is unable to exclude non-neutral behaviour. Furthermore, experimental factors can make a non-neutral clone size distribution appear neutral. We validate these principles with a new experimental dataset showing that when experiments are appropriately designed, the first incomplete moment can be a useful indicator of non-neutral competition. Finally, we discuss the complex relationship between mutant clone sizes and genetic selection.
癌症源自正常组织中突变的细胞。体细胞突变是否改变正常细胞的动力学是理解癌症风险和指导减少风险干预措施的关键。对正常人类眼睑皮肤中携带与癌症相关突变的克隆大小分布的第一个不完全矩进行的分析与中性漂移很好地吻合，表明突变不会影响细胞命运。然而，这一观点与同一数据集中的遗传证据相矛盾，该证据表明，一部分突变受到强烈的正选择。这意味着携带这些突变的细胞相对于正常细胞具有竞争优势，导致组织内的克隆大量扩张。在正常上皮中，克隆生长受到增殖区室的有限大小和与周围细胞竞争的限制。我们表明，如果考虑到这些因素，克隆大小分布的第一个不完全矩无法排除非中性行为。此外，实验因素可以使非中性克隆大小分布看起来是中性的。我们使用一个新的实验数据集验证了这些原则，表明当实验设计合理时，第一个不完全矩可以成为非中性竞争的有用指标。最后，我们讨论了突变克隆大小和遗传选择之间的复杂关系。
