Relative Telomere Length Change in Colorectal Carcinoma and Its Association with Tumor Characteristics, Gene Expression and Microsatellite Instability.

Abstract

Simple SummaryTelomeres are specialized repeat DNA sequences at the ends of each chromosome. The primary function of telomeres is to prevent genomic instability. Telomeres shorten with every cell division. The role of relative telomere length (RTL) change in colorectal cancer (CRC) is not fully understood. We studied RTL in CRC tissue and adjacent normal tissue from the same patients (n = 165). We found significant shortening of RTL in cancer tissue, irrespective of age group, gender, tumor pathology, location and microsatellite instability (MSI) status. However, shortening was more pronounced in low-grade tumors and in the presence of MSI. Gene expression data suggested an association of telomere shortening with rapid cell division (upregulation of DNA replication and cyclin-dependent kinase genes), as well as downregulation of apoptosis genes. CRC tissue showed upregulation of some telomere maintenance genes.We compared tumor and adjacent normal tissue samples from 165 colorectal carcinoma (CRC) patients to study change in relative telomere length (RTL) and its association with different histological and molecular features. To measure RTL, we used a Luminex-based assay. We observed shorter RTL in the CRC tissue compared to paired normal tissue (RTL 0.722 ± SD 0.277 vs. 0.809 ± SD 0.242, p = 0.00012). This magnitude of RTL shortening (by ~0.08) in tumor tissue is equivalent to RTL shortening seen in human leukocytes over 10 years of aging measured by the same assay. RTL was shorter in cancer tissue, irrespective of age group, gender, tumor pathology, location and microsatellite instability (MSI) status. RTL shortening was more prominent in low-grade CRC and in the presence of microsatellite instability (MSI). In a subset of patients, we also examined differential gene expression of (a) telomere-related genes, (b) genes in selected cancer-related pathways and (c) genes at the genome-wide level in CRC tissues to determine the association between gene expression and RTL changes. RTL shortening in CRC was associated with (a) upregulation of DNA replication genes, cyclin dependent-kinase genes (anti-tumor suppressor) and (b) downregulation of “caspase executor”, reducing apoptosis.