TERCpolymorphisms are associated both with susceptibility to colorectal cancer and with longer telomeres

Abstract

Background and aimsShorter telomeres have been associated with increased risk of malignancy, including colorectal cancer (CRC). Telomere length is heritable and may be an intermediate phenotype linked to genetic susceptibility to CRC.MethodsIn a large sample, the study investigated whether candidate single nucleotide polymorphisms (SNP) in ‘telomere biology’ genes were associated with telomere length in leucocytes. SNP associated with an increased risk of CRC were searched for separately.ResultsCarriers of the common allele at SNP rs10936599, near the telomerase RNA component (TERC) locus, had significantly longer telomeres. It was independently found that the same rs10936599 allele was associated with increased risk of both CRC and colorectal adenomas. Neither telomere length nor CRC risk was associated with variation near telomerase reverse transcriptase or other telomere biology genes. In silico analysis showed that SNP rs2293607 was strongly correlated with rs10936599, mapped within TERC transcripts, had a predicted effect on messenger RNA folding and lay at a reported transcription factor binding site. TERC mRNA were expressed, differing only at the alleles of rs2293607, in CRC cell line HCT116. The long-telomere/CRC-risk allele was associated with higher levels of TERC mRNA and the formation of longer telomeres.ConclusionsCommon genetic variation at TERC is associated with both longer telomeres and an increased risk of CRC, a potential mechanism being reduced levels of cell senescence or death. This finding is somewhat paradoxical, given retrospective studies reporting that CRC cases have shorter telomeres than controls. One possibility is that that association actually results from poorer survival in patients with longer telomeres.

Leukocyte Telomere Length in Relation to Pancreatic Cancer Risk: A Prospective Study

“…Using nonlinear methods, we observed a suggestive U-shape risk pattern between LTL and pancreatic cancer as already observed by Skinner and colleagues (14). Although several important risk factors for cancer, such as age and smoking, have been reported to be associated with shorter LTL, findings of a positive association between longer LTL and cancer risk are also plausible, in view of reports that short telomeres may induce cellular senescence, whereas longer telomeres generally mark actively reproducing cells that are at an increased risk of acquiring tumor-causing mutations (46). In agreement with the hypothesis that longer telomere increase cancer risk, a recent report by RoblesEspinoza and colleagues (47) describes a mutation in the protection of telomeres (POT1) gene that predisposes to familial melanoma and that is strongly associated with longer telomeres.…”

Risk of multiple myeloma is associated with polymorphisms within telomerase genes and telomere length

“…This is consistent with the same observation we made for TERT-rs2242652, and it is corroborated by similar findings from a recent study on colorectal cancer. 42 Longer telomeres might be a marker of an actively reproducing cell that has an increased chance of acquiring tumorcausing mutations. 42 The association of genetic variability and longer telomere could be of a particular importance in MM since telomerase reactivation and telomerase-mediated elongation of shorter telomeres is a feature of multiple myeloma and because there is an ongoing research on a possible TERT inhibition as a therapeutic approach in MM.…”

“…42 Longer telomeres might be a marker of an actively reproducing cell that has an increased chance of acquiring tumorcausing mutations. 42 The association of genetic variability and longer telomere could be of a particular importance in MM since telomerase reactivation and telomerase-mediated elongation of shorter telomeres is a feature of multiple myeloma and because there is an ongoing research on a possible TERT inhibition as a therapeutic approach in MM. 42 This study has several limitations, first of all we did not use an array to perform the genotyping and we could not take into account ancestry informative markers and therefore we cannot exclude a small proportion of outliers in the population.…”

“…42 The association of genetic variability and longer telomere could be of a particular importance in MM since telomerase reactivation and telomerase-mediated elongation of shorter telomeres is a feature of multiple myeloma and because there is an ongoing research on a possible TERT inhibition as a therapeutic approach in MM. 42 This study has several limitations, first of all we did not use an array to perform the genotyping and we could not take into account ancestry informative markers and therefore we cannot exclude a small proportion of outliers in the population. However it is unlikely that a small number of nonCaucasians would change the results masking a potentially true association or highlighting a spurious one, as suggested by the fact that we replicate the findings by Chubb et al We have not included all the polymorphic variants present in the regions, even though we have a representation, through tagging, of more than 90% of the common genetic variability of the TERT and TERC loci.…”

Leukocyte telomere length‐related genetic variants in 1p34.2 and 14q21 loci contribute to the risk of esophageal squamous cell carcinoma

“…1 However, in normal human leukocytes without or with little activity of telomerase, telomere length decreases with age at a rate of 20-40 base pairs (bp) per year. 5,6 Interestingly, short leukocyte telomere length has been associated with significantly increased risk to developing several cancers, including esophageal cancer, bladder cancer, renal cancer, breast cancer, ovarian cancer and colorectal cancer, [7][8][9][10][11][12][13][14][15][16][17] highlighting the predictive role of leukocyte telomere length in cancer pathogeneses.…”