Using DNA Methylation Patterns to Infer Tumor Ancestry
Using DNA Methylation Patterns to Infer Tumor Ancestry
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DOI：
10.1371/journal.pone.0012002
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发表时间：
2010-08-09
期刊：
影响因子：
3.7
通讯作者：
Siegmund, Kimberly D.
中科院分区：
文献类型：
--
作者：
Hong, You Jin;Marjoram, Paul;Siegmund, Kimberly D.
背景：由于连续观察不切实际，人类肿瘤的确切生长方式尚不确定。重建单个人类癌症历史的一种方法是分析其细胞之间的当前基因组变异。平均而言，变异越大，距离最后一个克隆进化周期的时间就越长（“分子钟假说”）。在这里，我们分析乘客的DNA甲基化模式，从对侧的12个主要的人类结直肠癌（CRC），以评估是否变化（表观等位基因之间的成对距离）是一致的，与一个单一的克隆扩张transformation.Methodology/主要调查结果：数据从12个主要的CRC进行比较，表观基因组数据模拟下一个单一的克隆扩张的各种可能的增长情况。我们发现，对于许多不同的增长率，一个单一的克隆扩张可以解释12个CRC中的11个的种群变异。在八个CRC中，来自不同腺体的细胞都是等距相关的，并且从同一肿瘤半部分取样的细胞看起来并不比从相对肿瘤半部分取样的细胞更密切相关。在这些肿瘤中，生长似乎与单一的“克隆性”扩增一致。在三个CRC中，表观遗传距离的变化在两侧之间是不同的，但是这种不对称性可以通过单个克隆扩增来解释，其中肿瘤的一个区域比另一个区域经历了更多的细胞分裂。在一个CRC的变化是复杂的，不一致的一个简单的单克隆expansion.Conclusions：而不是一系列的克隆扩张后，转化，这些结果表明，表观遗传变异的原发性CRC中的癌细胞几乎总是可以解释由一个单一的克隆扩张。
Background: Exactly how human tumors grow is uncertain because serial observations are impractical. One approach to reconstruct the histories of individual human cancers is to analyze the current genomic variation between its cells. The greater the variations, on average, the greater the time since the last clonal evolution cycle ("a molecular clock hypothesis''). Here we analyze passenger DNA methylation patterns from opposite sides of 12 primary human colorectal cancers (CRCs) to evaluate whether the variation (pairwise distances between epialleles) is consistent with a single clonal expansion after transformation.Methodology/Principal Findings: Data from 12 primary CRCs are compared to epigenomic data simulated under a single clonal expansion for a variety of possible growth scenarios. We find that for many different growth rates, a single clonal expansion can explain the population variation in 11 out of 12 CRCs. In eight CRCs, the cells from different glands are all equally distantly related, and cells sampled from the same tumor half appear no more closely related than cells sampled from opposite tumor halves. In these tumors, growth appears consistent with a single "symmetric'' clonal expansion. In three CRCs, the variation in epigenetic distances was different between sides, but this asymmetry could be explained by a single clonal expansion with one region of a tumor having undergone more cell division than the other. The variation in one CRC was complex and inconsistent with a simple single clonal expansion.Conclusions: Rather than a series of clonal expansion after transformation, these results suggest that the epigenetic variation of present-day cancer cells in primary CRCs can almost always be explained by a single clonal expansion.