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

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 (P < 0.0001). Moreover, in normal tissues, but not in tumours, telomere length inversely correlated with age (r = -0.24, P = 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 = 0.027). Furthermore, telomere length differed according to tumour location, being longer in rectal cancers (P = 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. British Journal of Cancer (2010) 102, 1300-1305. doi: 10.1038/sj.bjc.6605644 www.bjcancer.com (C) 2010 Cancer Research UK