Telomeres and telomere dynamics: relevance to cancers of the GI tract

Abstract

Aberrations in telomere length and telomere maintenance contribute to cancer development. In this article, we review the basic principles of telomere length in normal and tumor tissue and the presence of the two main telomere maintenance pathways as they pertain to gastrointestinal tract cancer. Peripheral blood telomeres are shorter in patients with many types of gastrointestinal tract cancers. Telomere length in tumor DNA also appears to shorten early in cancer development. Tumor telomere shortening is often accompanied by telomerase activation to protect genetically damaged DNA from normal cell senescence or apoptosis, allowing immortalized but damaged DNA to persist. Alternative lengthening of telomeres is another mechanism used by cancer to maintain telomere length in cancer cells. Telomerase and alternative lengthening of telomeres activators and inhibitors may become important chemopreventive or chemotherapeutic agents as our understanding of telomere biology, specific telomere-related phenotypes and its relationship to carcinogenesis increases.

Keywords::

• alternative lengthening of telomeres
• cancer
• cancer risk
• telomerase
• telomere maintenance genes
• telomeres
• TERT

Financial & competing interests disclosure

LA Boardman is supported by the National Cancer Institute (RO-1 CA132718 and RO-1 CA 170357) and the National Institute of Diabetes and Digestive and Kidney Diseases (P30 DK084567 Mayo Clinic Center for Cell Signaling in Gastroenterology). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• • Four of the ten most common cancers worldwide arise within the GI tract.

• • Telomeres are the caps of linear DNA that shorten with successive rounds of DNA replication, eventually leading to regulated cell senescence and apoptosis.

• • Depletion of constitutional telomere structure end-sequences is associated with an increased risk for some cancers.

• • Critical shortening of telomeres may lead to activation of telomerase in tumor cells, thus evading apoptosis and becoming more virulent.

• • Variations in telomere length in both tumor and peripheral blood DNA have been studied in almost all cancers within the GI tract.

• • Shorter telomere length in peripheral blood DNA is associated with an increased risk for many GI tract cancers.

• • Telomere length attrition starts in premalignant cells in many GI tract cancers, including Barrett’s associated esophageal adenocarcinoma, and pancreatic, colorectal and hepatocellular cancers.

• • Ongoing study of telomere length and maintenance mechanisms may lead to the development of targeted chemotherapeutics.

Notes

Data taken from [24,74,75,148].

Data taken from [36,44,164-169].

Data taken from [145,148,170,171].