Early Cancer Institute, University of Cambridge, Cambridge Biomedical Campus, Cambridge, Cambridgeshire, UK.
Nat Genet. 2023 Oct;55(10):1677-1685. doi: 10.1038/s41588-023-01490-z. Epub 2023 Sep 11.
Mosaic chromosomal alterations (mCAs) are common in cancers and can arise decades before diagnosis. A quantitative understanding of the rate at which these events occur, and their functional consequences, could improve cancer risk prediction and our understanding of somatic evolution. Using mCA clone size estimates from the blood of approximately 500,000 UK Biobank participants, we estimate mutation rates and fitness consequences of acquired gain, loss and copy-neutral loss of heterozygosity events. Most mCAs have moderate to high fitness effects but occur at a low rate, being more than tenfold less common than equivalently fit single-nucleotide variants. Notable exceptions are mosaic loss of X and Y, which we estimate have roughly 1,000-fold higher mutation rates than autosomal mCAs. Although the way in which most mCAs increase in prevalence with age is consistent with constant growth rates, some mCAs exhibit different behavior, suggesting that their fitness may depend on inherited variants, extrinsic factors or distributions of fitness effects.
镶嵌染色体改变（mCAs）在癌症中很常见，并且可能在诊断前数十年就出现。定量了解这些事件发生的速度及其功能后果，可以提高癌症风险预测和我们对体细胞进化的理解。我们利用来自约 500,000 名英国生物库参与者的血液中的 mCA 克隆大小估计值，估计了获得性增益、缺失和非等位基因杂合性丢失事件的突变率和适应度后果。大多数 mCAs 具有中度到高度的适应度效应，但发生的频率较低，比等效适应度的单核苷酸变体低十倍以上。值得注意的例外是 X 和 Y 的镶嵌性丢失，我们估计它们的突变率比常染色体 mCAs 高约 1000 倍。尽管大多数 mCAs 随年龄增长的流行方式与恒定的增长率一致，但有些 mCAs 表现出不同的行为，这表明它们的适应度可能取决于遗传变异、外在因素或适应度效应的分布。
