Integrated Multiregional Analysis Proposing a New Model of Colorectal Cancer Evolution.
Integrated Multiregional Analysis Proposing a New Model of Colorectal Cancer Evolution.
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DOI：
10.1371/journal.pgen.1005778
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发表时间：
2016-02
期刊：
影响因子：
4.5
通讯作者：
Mimori K
中科院分区：
文献类型：
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作者：
Uchi R;Takahashi Y;Niida A;Shimamura T;Hirata H;Sugimachi K;Sawada G;Iwaya T;Kurashige J;Shinden Y;Iguchi T;Eguchi H;Chiba K;Shiraishi Y;Nagae G;Yoshida K;Nagata Y;Haeno H;Yamamoto H;Ishii H;Doki Y;Iinuma H;Sasaki S;Nagayama S;Yamada K;Yachida S;Kato M;Shibata T;Oki E;Saeki H;Shirabe K;Oda Y;Maehara Y;Komune S;Mori M;Suzuki Y;Yamamoto K;Aburatani H;Ogawa S;Miyano S;Mimori K
了解肿瘤内异质性在临床上很重要，因为它可能会通过促进进化适应而导致治疗失败。为此，我们分析了9个结直肠肿瘤中每个肿瘤的多个区域的基因组和表观基因组。观察到广泛的肿瘤间异质性，从中我们推断肿瘤的进化历史。首先，出现克隆共享的改变，其中CpG位点的C>T转换和CpG岛高甲基化相对富集。突变计数与患者年龄之间的相关性表明，早期获得的改变是由衰老引起的。在后期，亲本克隆被分支成许多亚克隆。在早期获得的改变中经常观察到已知的驱动改变，但在晚期获得的改变中很少。一致的是，我们的分支进化的计算模拟表明，广泛的肿瘤内异质性可以产生中性进化。总的来说，我们提出了一个新的模型，结直肠癌的演变，这是有用的理解和面对这种异质性疾病。癌症是异质性疾病;不同患者的每个肿瘤具有不同的癌症基因组。此外，还存在另一个层次的异质性：即使是一个肿瘤也含有多个遗传上不同的亚克隆。这种瘤内异质性可能是治疗困难的原因之一，对它的理解在临床上是必要的。在这项研究中，我们通过分析从地理上分离的9个结直肠肿瘤区域获得的样本来研究结直肠癌的肿瘤内异质性。我们的综合数据分析与计算机模拟相结合，强烈表明，克隆共享的改变后，积累了老化，许多亚克隆产生的中性进化。重要的是，这一观点可以解释癌症的稳健性和可进化性：诱导环境变化的治疗作用将使许多中性突变中的一些转化为赋予治疗抗性的驱动基因。我们相信，这项研究不仅提供了深入了解结直肠癌的发病机制，但也构成了一个新的基础，设计治疗策略。
Understanding intratumor heterogeneity is clinically important because it could cause therapeutic failure by fostering evolutionary adaptation. To this end, we profiled the genome and epigenome in multiple regions within each of nine colorectal tumors. Extensive intertumor heterogeneity is observed, from which we inferred the evolutionary history of the tumors. First, clonally shared alterations appeared, in which C>T transitions at CpG site and CpG island hypermethylation were relatively enriched. Correlation between mutation counts and patients’ ages suggests that the early-acquired alterations resulted from aging. In the late phase, a parental clone was branched into numerous subclones. Known driver alterations were observed frequently in the early-acquired alterations, but rarely in the late-acquired alterations. Consistently, our computational simulation of the branching evolution suggests that extensive intratumor heterogeneity could be generated by neutral evolution. Collectively, we propose a new model of colorectal cancer evolution, which is useful for understanding and confronting this heterogeneous disease. Cancer is heterogeneous disease; each tumor in different patients has different cancer genomes. Furthermore, another level of heterogeneity exists: even a single tumor harbors multiple genetically distinct subclones. This intratumor heterogeneity is presumably one of causes of therapeutic difficulty, and its understanding is clinically necessary. In this study, we investigated intratumor heterogeneity in colorectal cancer by analyzing sample obtained from geographically separated regions of 9 colorectal tumors. Our integrated data analyses combined with computational simulation strongly suggest that, after clonally shared alterations were accumulated by aging, numerous subclones were generated by neutral evolution. Importantly, this view can explain the robustness and evolvability of cancer: therapeutic action inducing an environmental change would convert some of the numerous neutral mutations to driver genes that confer therapeutic resistance. We believe that this study not only provides insights into colorectal cancer pathogenesis, but also constitutes a new basis for designing therapeutic strategies.