Chromosomal instability in ulcerative colitis is related to telomere shortening
Chromosomal instability in ulcerative colitis is related to telomere shortening
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DOI：
10.1038/ng989
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发表时间：
2002-10-01
期刊：
影响因子：
30.8
通讯作者：
Rabinovitch, PS
中科院分区：
文献类型：
--
作者：
O'Sullivan, JN;Bronner, MP;Rabinovitch, PS
溃疡性结肠炎是一种结肠慢性炎症性疾病，与结直肠癌的高风险相关（1），认为结直肠癌是通过基因组不稳定性发展的（2）。我们认为，在溃疡性结肠炎中观察到的快速细胞更新和氧化损伤可能加速端粒缩短（3），从而增加染色体末端融合的可能性（4），导致染色质桥断裂和融合的周期（5，6）以及与肿瘤细胞进展相关的染色体不稳定性（7，8）。在这里，我们使用定量荧光原位杂交来比较染色体畸变和端粒缩短的非异型增生粘膜从受溃疡性结肠炎影响的个人，无论是（UC进展者）或没有（UC非进展者）异型增生或癌症。染色体臂和着丝粒的丢失而非增加与端粒缩短高度相关。UC进展者的活检样本中染色体丢失比UC非进展者或无溃疡性结肠炎的对照个体中的染色体丢失更大，端粒更短。端粒缩短和染色体不稳定性之间的机制联系得到了UC进展者中比UC非进展者或对照个体中更高频率的后期桥-染色质桥断裂和融合的中间体（9）的支持。我们的研究表明，端粒长度与人类癌症前体的染色体不稳定性相关。
Ulcerative colitis, a chronic inflammatory disease of the colon, is associated with a high risk of colorectal carcinoma(1) that is thought to develop through genomic instability(2). We considered that the rapid cell turnover and oxidative injury observed in ulcerative colitis might accelerate telomere shortening(3), thereby increasing the potential of chromosomal ends to fuse(4), resulting in cycles of chromatin bridge breakage and fusion(5,6) and chromosomal instability associated with tumor cell progression(7,8). Here we have used quantitative fluorescence in situ hybridization to compare chromosomal aberrations and telomere shortening in non-dysplastic mucosa taken from individuals affected by ulcerative colitis, either with (UC progressors) or without (UC non-progressors) dysplasia or cancer. Losses, but not gains, of chromosomal arms and centromeres are highly correlated with telomere shortening. Chromosomal losses are greater and telomeres are shorter in biopsy samples from UC progressors than in those from UC non-progressors or control individuals without ulcerative colitis. A mechanistic link between telomere shortening and chromosomal instability is supported by a higher frequency of anaphase bridges-an intermediate in the breakage and fusion of chromatin bridges(9)-in UC progressors than in UC non-progressors or control individuals. Our study shows that telomere length is correlated with chromosomal instability in a precursor of human cancer.