Inferring clonal expansion and cancer stem cell dynamics from DNA methylation patterns in colorectal cancers
Inferring clonal expansion and cancer stem cell dynamics from DNA methylation patterns in colorectal cancers
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DOI：
10.1073/pnas.0810276106
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发表时间：
2009-03-24
影响因子：
11.1
通讯作者：
Shibata, Darryl
中科院分区：
文献类型：
--
作者：
Siegmund, Kimberly D.;Marjoram, Paul;Shibata, Darryl
癌症是克隆扩增，但一个单一的，转化的人类细胞如何生长成十亿细胞的肿瘤是不确定的，因为连续观察是不切实际的。潜在地，这段历史被秘密地记录在基因组中，基因组在转化后变得越来越多，多态性和物理分离。为了将物理与表观遗传成对距离相关联，从12个原发性结直肠癌的左侧和右侧取样2，000至10，000个细胞的小腺体片段，并通过亚硫酸氢盐测序测量2个富含CpG的区域的乘客甲基化。甲基化模式是多态性的，但同一肿瘤的不同部位之间的差异是相似的，与相对各向同性或“平坦”克隆扩增，可以模拟快速初始人口扩增一致。甲基化模式过于多样化，与非常罕见的癌症干细胞不一致，但与每个癌腺的多个（约4至1，000个）长寿癌症干细胞谱系更一致。我们的研究说明了从人类癌症基因组中的表观遗传乘客变异中重建人类癌症未受干扰的生物学的潜力。
Cancers are clonal expansions, but how a single, transformed human cell grows into a billion-cell tumor is uncertain because serial observations are impractical. Potentially, this history is surreptitiously recorded within genomes that become increasingly numerous, polymorphic, and physically separated after transformation. To correlate physical with epigenetic pairwise distances, small 2,000- to 10,000-cell gland fragments were sampled from left and right sides of 12 primary colorectal cancers, and passenger methylation at 2 CpG-rich regions was measured by bisulfite sequencing. Methylation patterns were polymorphic but differences were similar between different parts of the same tumor, consistent with relatively isotropic or "flat'' clonal expansions that could be simulated by rapid initial population expansions. Methylation patterns were too diverse to be consistent with very rare cancer stem cells but were more consistent with multiple (approximate to 4 to 1,000) long-lived cancer stem cell lineages per cancer gland. Our study illustrates the potential to reconstruct the unperturbed biology of human cancers from epigenetic passenger variations in their present-day genomes.