Abstract 3203: Ulcerative colitis-associated colorectal cancer arises in a field of short telomeres, increased senescence, and inflammation
Authors: Risques Rosa Ana , Lai Lisa A. , Bronner Mary P. , Rabinovitch Peter S. , Brentnall Teresa A. 
Published: February 2011

Introduction: Around 10% of patients with ulcerative colitis (UC) will develop colorectal cancer in their lifetime. The tumorigenic process involves progression from non-dysplastic colonic epithelium to dysplasia (indefinite, low grade (LGD) or high grade (HGD)), and cancer. We have previously demonstrated that the non-dysplastic epithelium from UC patients with HGD or cancer (UC progressors) harbors molecular abnormalities, but the extent of this field effect is unknown. Our goal is to characterize the field effect of telomere shortening, senescence, and inflammation in the colon of UC progressors in order to determine the role of these alterations in UC tumorigenesis and their potential as biomarkers of cancer risk.

Material and Methods: For 9 UC progressors an average of 7 biopsies (min 5, max 10) including HGD, LGD, and non-dysplastic normal appearing mucosa, were collected along the colon and analyzed for the following parameters: (1) telomere length: measured by Quantitative-PCR; (2) DNA damage: measured by immunofluorescence of γ-H2AX; (3) senescence: measured by immunofluorescence of Dec1; and (4) inflammation: measured by the classical pathological index of acute inflammation, the levels of lymphocytes in lamina propria, and the amount of lymphoid aggregates. In addition, we analyzed 5 biopsies collected along the colon from 4 UC non-progressors (patients without HGD or cancer) and 10 control biopsies from individuals without UC.

Results: Telomeres were significantly shorter in non-dysplastic biopsies of UC progressors compared to non-progressors and the shortening had a widespread field effect, as it was observed throughout the colon of UC progressors. However, telomere shortening was more pronounced in non-dysplastic biopsies located less than 10 cm from HGD or cancer. These biopsies also showed significantly higher levels of DNA damage, senescence, and lamina propria lymphocytes. Interestingly, LGD biopsies had the shortest telomeres and the highest levels of senescence and lamina propria lymphocytes, while HGD biopsies showed telomere lengthening and a significant decrease in senescence and lamina propria lymphocytes. In addition, high levels of lamina propria lymphocytes were associated with telomere shortening and senescence.

Conclusions: Our results indicate that there is a field effect of telomere shortening, DNA damage, senescence, and inflammation that is at least 10 cm in length, in the region where dysplasia and cancer arise. Telomeres lengthen and senescence is abrogated in the transition from LGD to HGD. The presence of telomere shortening in non-dysplastic epithelium along the colon of UC progressors suggests that it might have a potential value as a cancer risk biomarker.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3203.