Telomere shortening correlates to dysplasia but not to DNA aneuploidy in longstanding ulcerative colitis

Mariann Friis-Ottessen,Solveig Norheim-Andersen,Ole Petter F Clausen,Steen Kølvraa,Paula M De Angelis,Laila Bendix

doi:10.1186/1471-230x-14-8

Abstract

BackgroundUlcerative colitis (UC) is a chronic, inflammatory bowel disease which may lead to dysplasia and adenocarcinoma in patients when long-lasting. Short telomeres have been reported in mucosal cells of UC patients. Telomeres are repetitive base sequences capping the ends of linear chromosomes, and protect them from erosion and subsequent wrongful recombination and end-to-end joining during cell division. Short telomeres are associated with the development of chromosomal instability and aneuploidy, the latter being risk factors for development of dysplasia and cancer. Specifically, the abrupt shortening of one or more telomeres to a critical length, rather than bulk shortening of telomeres, seems to be associated with chromosomal instability.MethodsWe investigated possible associations between dysplasia, aneuploidy and telomere status in a total of eight lesions from each of ten progressors and four nonprogressors suffering from longstanding UC. We have analyzed mean telomere length by qPCR, as well as the amount of ultra-short telomeres by the Universal STELA method.ResultsAn increased amount of ultra-short telomeres, as well as general shortening of mean telomere length are significantly associated with dysplasia in longstanding UC. Furthermore, levels of ultra-short telomeres are also significantly increased in progressors (colons harbouring cancer/dysplasia and/or aneuploidy) compared to nonprogressors (without cancer/dysplasia/aneuploidy), whereas general shortening of telomeres did not show such associations.ConclusionsOur data suggest that ultra-short telomeres may be more tightly linked to colorectal carcinogenesis through development of dysplasia in UC than general telomere shortening. Telomere status was not seen to associate with DNA aneuploidy.

Highlights

Ulcerative colitis (UC) is a chronic, inflammatory bowel disease which may lead to dysplasia and adenocarcinoma in patients when long-lasting
Within the ten progressor colectomies we found a significant difference between the different degrees of dysplasia when low-grade dysplasia (LGD), high-grade dysplasia (HGD) and adenocarcinomas were combined (p = 0.033)
In a multivariable general linear model (GLM) where we tested for the effect of biopsy location, degree of dysplasia, DNA ploidy status and age at onset combined with duration of UC, we found that in the progressor colectomies, both location of the biopsy (p =0.006) and degree of dysplasia (p = 0.012) might be individually influential to the mean telomere length

Summary

Introduction

Ulcerative colitis (UC) is a chronic, inflammatory bowel disease which may lead to dysplasia and adenocarcinoma in patients when long-lasting. In 2003, Baird and colleagues presented the single telomere length analysis, STELA, that is able to detect the shortest telomeres in a sample [11]. This analysis was originally limited to the XpYp telomeres, but has since been extended to several autosomal chromosomes as well [12]. Bendix and colleagues presented a method in 2010 that provides an estimate of the load of ultra-short telomeres in a DNA sample This method is a version of the STELA, and was named the UniversalSTELA, as it is not limited to chromosomes with known subtelomeric composition [13]

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