Clinical Relevance of Telomere Status and Telomerase Activity in Colorectal Cancer.

Tamara Fernández-Marcelo,Antonio-José Torres-García,Pilar Iniesta,Andrés Sánchez-Pernaute,Irene Pascua,Carmen De Juan,Jacqueline Head

doi:10.1371/journal.pone.0149626

Abstract

The role of telomeres and telomerase in colorectal cancer (CRC) is well established as the major driving force in generating chromosomal instability. However, their potential as prognostic markers remains unclear. We investigated the outcome implications of telomeres and telomerase in this tumour type. We considered telomere length (TL), ratio of telomere length in cancer to non-cancer tissue (T/N ratio), telomerase activity and TERT levels; their relation with clinical variables and their role as prognostic markers. We analyzed 132 CRCs and paired non-cancer tissues. Kaplan-Meier curves for disease-free survival were calculated for TL, T/N ratio, telomerase activity and TERT levels. Overall, tumours had shorter telomeres than non-tumour tissues (P < 0.001) and more than 80% of CRCs displayed telomerase activity. Telomere lengths of non-tumour tissues and CRCs were positively correlated (P < 0.001). Considering telomere status and clinical variables, the lowest degree of telomere shortening was shown by tumours located in the rectum (P = 0.021). Regarding prognosis studies, patients with tumours showing a mean TL < 6.35 Kb experienced a significantly better clinical evolution (P < 0.001) and none of them with the highest degree of tumour telomere shortening relapsed during the follow-up period (P = 0.043). The mean TL in CRCs emerged as an independent prognostic factor in the Cox analysis (P = 0.017). Telomerase-positive activity was identified as a marker that confers a trend toward a poor prognosis. In CRC, our results support the use of telomere status as an independent prognostic factor. Telomere status may contribute to explaining the different molecular identities of this tumour type.

Highlights

Colorectal cancer (CRC) is the third most common cancer in men and the second in women worldwide[1]
The chromosomal instability (CIN) pathway is characterized by the accumulation of numerical or structural chromosomal abnormalities which causes the loss of onco-suppressor genes and the activation of oncogenes
Telomere length was analysed in a total of 264 colorectal tissue samples: 132 CRCs and their corresponding non-tumour samples

Summary

Introduction

Colorectal cancer (CRC) is the third most common cancer in men and the second in women worldwide[1]. Several factors are associated with a lower CRC probability, such as high physical activity and high intakes of dietary fiber, fish, nuts, dairy products, and fruits and vegetables. High body mass index and waist circumference, smoking, alcohol consumption, and red and processed meat intakes are related to a higher CRC risk [2,3,4]. Three pathways, not mutually exclusive and named by the cellular process which promotes them, have been implicated in the development of CRC. The chromosomal instability (CIN) pathway is characterized by the accumulation of numerical or structural chromosomal abnormalities which causes the loss of onco-suppressor genes and the activation of oncogenes. The microsatellite instability (MSI) pathway is defined as a deficient DNA Mismatch Repair System that causes unrepaired errors in the microsatellites (nucleotide repeat sequences). The CpG island methylator phenotype (CIMP) pathway exhibits gene silencing due to a widespread hypermethylation of CpG islands at several loci [6,7,8,9]

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