Chromosomal instability in ulcerative colitis is related to telomere shortening

被引:271
作者
O'Sullivan, JN
Bronner, MP
Brentnall, TA
Finley, JC
Shen, WT
Emerson, S
Emond, MJ
Gollahon, KA
Moskovitz, AH
Crispin, DA
Potter, JD
Rabinovitch, PS [1 ]
机构
[1] Univ Washington, Dept Pathol, Seattle, WA 98195 USA
[2] Univ Washington, Dept Med, Seattle, WA 98195 USA
[3] Univ Washington, Dept Biostat, Seattle, WA 98195 USA
[4] Univ Washington, Dept Surg, Seattle, WA 98195 USA
[5] Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA
基金
美国国家卫生研究院;
关键词
D O I
10.1038/ng989
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
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.
引用
收藏
页码:280 / 284
页数:5
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