Uchi Ryutaro, Takahashi Yusuke, Niida Atsushi, Shimamura Teppei, Hirata Hidenari, Sugimachi Keishi, Sawada Genta, Iwaya Takeshi, Kurashige Junji, Shinden Yoshiaki, Iguchi Tomohiro, Eguchi Hidetoshi, Chiba Kenichi, Shiraishi Yuichi, Nagae Genta, Yoshida Kenichi, Nagata Yasunobu, Haeno Hiroshi, Yamamoto Hirofumi, Ishii Hideshi, Doki Yuichiro, Iinuma Hisae, Sasaki Shin, Nagayama Satoshi, Yamada Kazutaka, Yachida Shinichi, Kato Mamoru, Shibata Tatsuhiro, Oki Eiji, Saeki Hiroshi, Shirabe Ken, Oda Yoshinao, Maehara Yoshihiko, Komune Shizuo, Mori Masaki, Suzuki Yutaka, Yamamoto Ken, Aburatani Hiroyuki, Ogawa Seishi, Miyano Satoru, Mimori Koshi
Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan.
Department of Otorhinolaryngology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
PLoS Genet. 2016 Feb 18;12(2):e1005778. doi: 10.1371/journal.pgen.1005778. eCollection 2016 Feb.
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.
了解肿瘤内异质性在临床上具有重要意义，因为它可能通过促进进化适应导致治疗失败。为此，我们对9个结直肠癌肿瘤中每个肿瘤的多个区域进行了基因组和表观基因组分析。观察到广泛的肿瘤间异质性，从中我们推断出肿瘤的进化历史。首先，出现了克隆共享改变，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。在晚期，一个亲本克隆分支成许多亚克隆。已知的驱动改变在早期获得的改变中经常观察到，但在晚期获得的改变中很少观察到。一致地，我们对分支进化的计算模拟表明，广泛的肿瘤内异质性可能由中性进化产生。总的来说，我们提出了一种新的结直肠癌进化模型，这有助于理解和应对这种异质性疾病。
