The landscape of somatic mutation in normal colorectal epithelial cells
The landscape of somatic mutation in normal colorectal epithelial cells
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DOI：
10.1038/s41586-019-1672-7
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发表时间：
2019-10-24
期刊：
影响因子：
64.8
通讯作者：
Stratton, Michael R.
中科院分区：
文献类型：
--
作者：
Lee-Six, Henry;Olafsson, Sigurgeir;Stratton, Michael R.
结直肠腺瘤-癌序列为理解导致癌症的连续体细胞遗传变化和随后的克隆扩增提供了一个范例框架（1）。然而，我们对结直肠肿瘤变化的早期阶段的理解（可能发生在形态正常的组织中）相对有限，就像大多数癌症类型一样。在这里，我们使用全基因组测序来分析来自42个个体的数百个正常隐窝。揭示了多个突变过程的特征;其中一些是普遍存在的和连续的，而另一些则仅在某些个体、某些隐窝或某些生命周期中发现。在中年人中，大约1%的正常结直肠隐窝中存在可能的驱动突变，这表明腺瘤和癌是形态正常结直肠上皮肿瘤变化的普遍过程的罕见结果。结直肠癌相对于正常细胞表现出显著增加的突变负担。正常结直肠细胞测序提供了对癌症基因组和克隆进化的定量见解。
The colorectal adenoma-carcinoma sequence has provided a paradigmatic framework for understanding the successive somatic genetic changes and consequent clonal expansions that lead to cancer(1). However, our understanding of the earliest phases of colorectal neoplastic changes-which may occur in morphologically normal tissue-is comparatively limited, as for most cancer types. Here we use whole-genome sequencing to analyse hundreds of normal crypts from 42 individuals. Signatures of multiple mutational processes were revealed; some of these were ubiquitous and continuous, whereas others were only found in some individuals, in some crypts or during certain periods of life. Probable driver mutations were present in around 1% of normal colorectal crypts in middle-aged individuals, indicating that adenomas and carcinomas are rare outcomes of a pervasive process of neoplastic change across morphologically normal colorectal epithelium. Colorectal cancers exhibit substantially increased mutational burdens relative to normal cells. Sequencing normal colorectal cells provides quantitative insights into the genomic and clonal evolution of cancer.