Ulcerative Colitis Is a Disease of Accelerated Colon Aging: Evidence From Telomere Attrition and DNA Damage

Risques, Rosa Ana; Lai, Lisa A.; Brentnall, Teresa A.; Li, Lin; Feng, Ziding; Gallaher, Jasmine L.; Mandelson, Margaret T.; Potter, John D.; Bronner, Mary P.; Rabinovitch, Peter S.

doi:10.1053/j.gastro.2008.04.008

Cited by 155 publications

(143 citation statements)

References 43 publications

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“…33,34 Especially in those with ulcerative colitis, hTERT overexpression has been associated with induction of CIN, 34 possibly an effect of oxidative damage secondary to inflammation. 35 Our results are in accordance with those of most of the aforementioned studies, as we found telomerase activity to be present in all normal colon tissue samples and in colon cancer tissue samples. Unfortunately, we did not have adenoma samples that could further enlighten the differences in telomerase activity and MLH1 expression in the various stages of CRC carcinogenesis.…”

Section: Discussionsupporting

confidence: 93%

Differences in telomerase activity between colon and rectal cancer

et al. 2014

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Differences in telomerase activity between colon and rectal cancerBackground: Colorectal cancer is one of the most common cancers and the third leading cause of cancer death in both sexes. The disease progresses as a multistep process and is associated with genetic alterations. One of the characteristic features of cancer is telomerase activation. We sought to evaluate the differences in telomerase activity between colon cancer and adjacent normal tissue and to correlate the differences in telomerase activity between different locations with clinicopathological factors and survival. Methods:Matched colon tumour samples and adjacent normal mucosa samples 10 cm away from the tumour were collected during colectomy. We assessed telomerase activity using real time polymerase chain reaction. Several pathological characteristics of tumours, including p53, Ki-67, p21, bcl2 and MLH1 expression were also studied. Results:We collected samples from 49 patients. There was a significantly higher telomerase activity in colon cancer tissue than normal tissue. Adenocarcinomas of the right colon express significantly higher telomerase than left-side cancers. Colon cancers and their adjacent normal tissue had significantly more telomerase and were more positive to MLH1 than rectal cancers. The expression of p53 negatively correlated to telomerase activity and was linked to better patient survival. Conclusion:Colon and rectal cancers seem to have different telomerase and MLH1 profiles, and this could be another factor for their different biologic and clinical behaviour and progression. These results support the idea that the large bowel cannot be considered a uniform organ, at least in the biology of cancer.Contexte : Le cancer colorectal est l'un des cancers les plus répandus; il arrive au troisième rang des décès attribuables au cancer chez les hommes et les femmes. La maladie progresse en plusieurs étapes et est associée à des anomalies génétiques. L'une des principales caractéristiques du cancer est l'activation de la télomérase. Nous avons voulu évaluer les différences d'activité de la télomérase entre les tissus touchés par le cancer du côlon et les tissus adjacents normaux afin d'établir une corrélation entre les différences d'activité de la télomérase selon la localisation d'une part et les facteurs clinicopathologiques et la survie d'autre part. Méthodes :Lors de colectomies, nous avons recueilli des échantillons tissulaires jumelés de tumeur du côlon et de muqueuse adjacente normale à 10 cm du foyer tumoral. Nous avons mesuré l'activité de la télomérase à l'aide de la réaction en chaîne de la polymérase en temps réel. Plusieurs caractéristiques pathologiques des tumeurs ont aussi été analysées, y compris l'expression des gènes p53, Ki-67, p21, bcl2 et MLH1. Résultats :Nous avons recueilli des échantillons auprès de 49 patients. Nous avons noté une activité nettement plus intense de la télomérase dans les tissus touchés par le cancer du côlon que dans les tissus normaux. Les adénocarcinomes du côlon ascendant expriment une...

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Section: Discussionsupporting

confidence: 93%

Differences in telomerase activity between colon and rectal cancer

et al. 2014

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“…It has been proposed that telomere shortening with age may increase the risk of cancer (Blasco, 2005;Risques et al, 2008); this concept may be supported by our results, as telomere shortening between normal and neoplastic tissues was found to be inversely correlated with age. Although telomere length in somatic cells primarily reflects cellular proliferation, telomere length in tumour cells reflects the balance between cellular proliferation with telomere loss and telomerase activity with de novo synthesis of telomeric sequences.…”

Section: Discussionsupporting

confidence: 89%

Relationship between telomere shortening, genetic instability, and site of tumour origin in colorectal cancers

et al. 2010

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BACKGROUND: Telomeres, located at chromosome ends, are progressively shortened during each cell cycle by replication-dependent loss of DNA termini. Although maintenance of telomere length is critical for cell-replicative potential and tumourigenesis, the erosion of telomeres can lead to genetic instability, a pivotal mechanism in the neoplastic process. PATIENTS AND METHODS: A total of 118 colorectal cancer (CRC) samples (53 right-colon, 30 left-colon, and 35 rectal tumours) and corresponding adjacent non-cancerous tissues were evaluated for telomere length, p53 mutation, and microsatellite instability (MSI). Telomere length was estimated by real-time PCR. RESULTS: Telomeres were significantly shorter in CRCs than in adjacent tissues, regardless of tumour stage and grade, site, or genetic alterations (Po0.0001). Moreover, in normal tissues, but not in tumours, telomere length inversely correlated with age (r ¼ À0.24, P ¼ 0.017). Telomere length in CRCs did not differ with tumour progression or p53 status; however, in CRCs carrying the wild-type p53, telomeres were significantly shorter in tumours with MSI than in those with stable microsatellites (P ¼ 0.027). Furthermore, telomere length differed according to tumour location, being longer in rectal cancers (P ¼ 0.03). CONCLUSIONS: These findings suggest that telomere shortening is a key initial event in colorectal carcinogenesis. The extent of telomere erosion is related to tumour origin site and may be influenced by the mismatch repair pathway.

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“…15 We postulate that replicative exhaustion and subsequent cellular senescence of the intestinal stem cell compartment can at least partially explain clinical refractoriness of aGVHD despite sufficient immunosuppressive treatment. Further studies focusing on the analysis of nonrefractory aGVHD (milder disease) patient material, which is difficult to obtain because of obvious reasons, are warranted to reveal whether the degree of TL can be reversed in this patient population.…”

Section: Resultsmentioning

confidence: 98%