Genotypic and phenotypic changes in the colonic mucosa of patients suffering from longstanding ulcerative colitis

Ulcerative colitis (UC) is an inflammatory bowel disease, associated with increased lifetime risk of developing colorectal cancer. UC-associated cancers progress through increasing levels of dysplasia, accompanied by important molecular changes, such as chromosomal instability and aneuploidy. Aneuploidy is a common feature in UC-colonic mucosa, and is often seen to precede dysplasia and cancer. Approximately 10 % of UC-patients will develop malignancies through the colon within 10 years of disease duration. These patients have increased risk of developing cancer, and are termed progressors. Patients with no malignant changes to the colonic mucosa are termed non-progressors, and have no increased risk of cancer development. The molecular mechanisms underlying malignant progression in UC are not fully elucidated, but are suggested to involve increasing degrees of chromosomal instability, telomere shortening and a defect spindle assembly checkpoint. Chronic inflammation elevates the level of oxidative stress. Oxidative stress can create ultra-short telomeres through single-or double strand chromosome breaks. A single ultra-short telomere may induce aneuploidy. We investigated the amounts of ultra-short telomeres in UC-colonic mucosal cells of both progressors and nonprogressors, applying a method for estimating the amount of ultra-short telomeres, the Universal STELA. We found that progressors have higher levels of ultra-short telomeres in the colonic mucosal lining compared to non-progressors. Our results provide new information concerning the investigation of the molecular underpinnings of cancer progression in UC, and may be of use in detecting a progressor at an early stage of the disease development

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

Background Ulcerative 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. Methods We 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. Results An 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. Conclusions Our 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