Ewing Adam D, Gacita Anthony, Wood Laura D, Ma Florence, Xing Dongmei, Kim Min-Sik, Manda Srikanth S, Abril Gabriela, Pereira Gavin, Makohon-Moore Alvin, Looijenga Leendert H J, Gillis Ad J M, Hruban Ralph H, Anders Robert A, Romans Katharine E, Pandey Akhilesh, Iacobuzio-Donahue Christine A, Vogelstein Bert, Kinzler Kenneth W, Kazazian Haig H, Solyom Szilvia
Mater Research Institute, University of Queensland, Woolloongabba, Queensland 4102, Australia;
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA;
Genome Res. 2015 Oct;25(10):1536-45. doi: 10.1101/gr.196238.115. Epub 2015 Aug 10.
Somatic L1 retrotransposition events have been shown to occur in epithelial cancers. Here, we attempted to determine how early somatic L1 insertions occurred during the development of gastrointestinal (GI) cancers. Using L1-targeted resequencing (L1-seq), we studied different stages of four colorectal cancers arising from colonic polyps, seven pancreatic carcinomas, as well as seven gastric cancers. Surprisingly, we found somatic L1 insertions not only in all cancer types and metastases but also in colonic adenomas, well-known cancer precursors. Some insertions were also present in low quantities in normal GI tissues, occasionally caught in the act of being clonally fixed in the adjacent tumors. Insertions in adenomas and cancers numbered in the hundreds, and many were present in multiple tumor sections, implying clonal distribution. Our results demonstrate that extensive somatic insertional mutagenesis occurs very early during the development of GI tumors, probably before dysplastic growth.
已证明体细胞L1逆转座事件发生在上皮癌中。在此，我们试图确定胃肠道（GI）癌发生过程中体细胞L1插入的早期发生情况。利用L1靶向重测序（L1-seq），我们研究了由结肠息肉引发的4例结直肠癌、7例胰腺癌以及7例胃癌的不同阶段。令人惊讶的是，我们不仅在所有癌症类型及其转移灶中发现了体细胞L1插入，还在结肠腺瘤（众所周知的癌症前体）中发现了体细胞L1插入。在正常GI组织中也有少量插入，偶尔会在相邻肿瘤中被克隆固定。腺瘤和癌中的插入数以百计，且许多存在于多个肿瘤切片中，这意味着克隆分布。我们的结果表明，广泛的体细胞插入诱变在GI肿瘤发生的早期就已发生，可能在发育异常生长之前。
