Institute of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, UK.
J Natl Cancer Inst. 2013 Aug 21;105(16):1202-11. doi: 10.1093/jnci/djt191. Epub 2013 Aug 5.
Telomere shortening, dysfunction, and fusion may facilitate the acquisition of large-scale genomic rearrangements, driving clonal evolution and tumor progression. The relative contribution that telomere dysfunction and/or APC mutation play in the chromosome instability that occurs during colorectal tumorigenesis is not clear.
We used high-resolution telomere length and fusion analysis to analyze 85 adenomatous colorectal polyps obtained from 10 patients with familial adenomatous polyposis and a panel of 50 colorectal carcinomas with patient-matched normal colonic mucosa. Telomerase activity was determined using the telomeric repeat amplification protocol. Array-CGH was used to detect large-scale genomic rearrangements. Pearson correlation and Student t test were used, and all statistical tests were two-sided.
Despite the presence of telomerase activity, we observed apparent telomere shortening in colorectal polyps that correlated with large-scale genomic rearrangements (P < .0001) but was independent of polyp size and indistinguishable from that observed in colorectal carcinomas (P = .82). We also observed apparent lengthening of telomeres in both polyps and carcinomas. The extensive differences in mean telomere length of up to 4.6kb between patient-matched normal mucosa and polyps were too large to be accounted for by replicative telomere erosion alone. Telomere fusion events were detected in both polyps and carcinomas; the mutational spectrum accompanying fusion was consistent with alternative nonhomologous end joining.
Telomere length distributions observed in colorectal polyps reflect the telomere length composition of the normal originating cells from which clonal growth was initiated. Originating cells containing both short telomeres and APC mutations may give rise to polyps that exhibit short telomeres and are prone to telomere dysfunction, driving genomic instability and progression to malignancy. J Natl Cancer Inst;2013;105:1202-1211.
端粒缩短、功能障碍和融合可能促进大规模基因组重排的发生，从而推动克隆进化和肿瘤进展。端粒功能障碍和（或） APC 突变在结直肠肿瘤发生过程中导致的染色体不稳定性中所起的相对作用尚不清楚。
我们使用高分辨率端粒长度和融合分析，分析了来自 10 例家族性腺瘤性息肉病患者的 85 个腺瘤性结直肠息肉和 50 个结直肠癌患者匹配的正常结肠黏膜的样本。使用端粒重复扩增协议测定端粒酶活性。使用 array-CGH 检测大规模基因组重排。采用 Pearson 相关和学生 t 检验，所有统计检验均为双侧检验。
尽管存在端粒酶活性，我们观察到结直肠息肉中存在明显的端粒缩短，且与大规模基因组重排相关（P＜0.0001），但这种缩短与息肉大小无关，且与结直肠癌中的端粒缩短无区别（P=0.82）。我们还观察到息肉和癌组织中端粒的明显延长。患者匹配的正常黏膜与息肉之间长达 4.6kb 的端粒长度差异非常大，仅凭复制性端粒侵蚀无法解释这种差异。在息肉和癌组织中均检测到端粒融合事件；融合伴随的突变谱与替代性非同源末端连接一致。
结直肠息肉中观察到的端粒长度分布反映了起始克隆生长的正常起始细胞的端粒长度组成。含有短端粒和 APC 突变的起始细胞可能导致表现出短端粒且易于发生端粒功能障碍的息肉，从而导致基因组不稳定性并进展为恶性肿瘤。
国家癌症研究所杂志；2013；105：1202-1211
