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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Inferring clonal expansion and cancer stem cell dynamics from DNA methylation patterns in colorectal cancers
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Inferring clonal expansion and cancer stem cell dynamics from DNA methylation patterns in colorectal cancers

机译:从DNA甲基化模式推断大肠癌的克隆扩增和癌症干细胞动力学

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摘要

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 (≈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.
机译:癌症是克隆性扩增,但是单个转化的人类细胞如何生长成十亿个细胞的肿瘤尚不确定,因为连续观察是不切实际的。潜在地,这种历史被秘密地记录在基因组中,该基因组在转化后变得越来越多,多态且在物理上分离。为了使物理距离与表观遗传学上的成对距离相关联,从12种原发性结直肠癌的左侧和右侧取样了2,000至10,000个细胞的小腺碎片,并通过亚硫酸氢盐测序测量了2个CpG富集区域的乘客甲基化。甲基化模式是多态性的,但是同一肿瘤的不同部分之间的差异相似,这与可以通过快速初始种群扩展模拟的相对各向同性或“平坦”的克隆扩展相一致。甲基化模式差异太大,无法与非常罕见的癌症干细胞相一致,但与每个癌体的多个(≈4到1,000个)长寿命癌症干细胞谱系更加一致。我们的研究表明了从人类现代基因组中表观遗传乘客变异中重建人类癌症无干扰生物学的潜力。

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  • 作者单位

    Department of Preventive Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA 90033;

    Department of Preventive Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA 90033;

    Department of Pathology, University of Southern California Keck School of Medicine, Los Angeles, CA 90033;

    Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089 Department of Oncology, University of Cambridge, Cambridge CB2 2XZ, United Kingdom;

    Department of Pathology, University of Southern California Keck School of Medicine, Los Angeles, CA 90033;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    progression; invasion; growth;

    机译:进步侵入;成长;

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