Telomere length differences between colorectal polyp subtypes: a colonoscopy-based case-control study

Colorectal cancer (CRC) is a multi-pathway disease; unique CRC pathways are associated with distinct polyp precursor lesions. Advanced adenomas are known precursor lesions to CRC within the adenoma-carcinoma pathway, while sessile serrated adenomas/polyps (SSA/Ps), are precursors on the serrated pathway [1]. Currently, colorectal polyps are not diagnosed until colonoscopy, an expensive and invasive procedure. Moreover, advanced adenomas are diagnosed in about 6% of those undergoing colonoscopy; rate of SSA/P diagnosis is lower [2]. If reliable biomarkers that enable risk stratification to identify those at highest risk for progression to CRC can be identified, patients could be triaged to tailored screening and surveillance regimes that coincide with their level of risk.

One such potential biomarker of interest is telomere length (TL). Telomeres, the DNA repeat sequences at ends of chromosomes, play an important role in maintaining genomic integrity [3]. Short TL has been evaluated as a biomarker for ageing, and age-related conditions, including cancers; particularly of the gastrointestinal tract [4]. The relationship between shortened telomeres and risk of sporadic colorectal cancers, however, is not yet clear. Here, we evaluate the association between TL and the risk for colorectal polyp subtypes.

Of the 190 study participants with available DNA specimens, 80 were classified as having adenomas, 33 as serrated polyps, 28 as having both adenomas and serrated polyps, and were compared to 49 polyp-free controls. Demographic comparisons between polyp subtype cases and controls are shown in Table 1. Participants with adenomas only were slightly older and more likely than controls to be male and former smokers. In contrast, study participants with serrated polyps only were more likely to be female, current/former smokers, and obese. Cases were similar to controls with respect to other lifestyle exposures such as their educational status, and anti-inflammatory drug use.

Table 2 presents the ORs and 95% CI for each colorectal polyp subtype outcomes according to shortest telomere tertile. Having TL in the shortest tertile (T/S ratio < 0.58) was associated with an increased risk of serrated polyps [adjusted OR(95%CI) =2.98 (1.15,7.77)] even after adjustment for confounding effects of age, sex, race, smoking status, body mass index, and use of anti-inflammatory drugs. Short TLs were also modestly and non-significantly associated with increased adenoma risk [OR(95% CI) =1.77 (0.81,3.88)] in adjusted models. When evaluated by lesion severity within each pathway, short telomeres appeared to be more strongly associated with advanced adenomas [OR(95% CI) = 1.90(0.76,4.73)] and sessile serrated polyps [OR(95% CI) = 3.82(0.86,16.86)], although these associations did not reach statistical significance. Lastly, we did not find any evidence for heterogeneity in the associations with short TL for adenomas vs. serrated polyps (p for heterogeneity =0.42) or for lesion severity comparisons within the adenoma and serrated pathways.

There are limited prior studies evaluating the association between shortened telomeres and colorectal neoplasia. Two case-control studies nested within large cohorts observed a lack of association between TL and CRC [7‐9]. Conversely, Pooley et al. have reported significantly shorter telomeres in circulating leukocytes among CRC cases than controls [10]. More recently, a large population-wide Danish study of over 47,000 individuals reported no association, while a Chinese study reported increased CRC risk with shorter TL [9, 11]. Summarizing these findings, a very recent meta-analysis noted that the available evidence is insufficient to understand the exact role of telomere length in the development of colorectal cancer, and highlighted the need for future studies [12]. Fewer studies have evaluated the relationship between colorectal cancer precursor lesions and TL. A recent report suggested an increased risk for advanced adenomas in persons with short leukocyte TL [13]; however, this study was relatively small (35 advanced adenomas cases) and did not evaluate the relationship with serrated polyps. Roger et al. reported in an experimental setting that extensive tissue telomere erosion may lead to chromosomal instability and initiation of CRC in polyps from familial adenomatous polyposis patients [14]. The authors hypothesize that this may be a potential mechanism resulting in chromosomal instability and malignant transformation. Another cross-sectional study found that TL in large adenoma lesions (> 2 cm) was significantly shorter than normal surrounding tissue from the same individuals [15]. Taken together, these studies suggest that telomere shortening may play a role in the development of both colorectal polyps and/or CRC. However, further studies are required to better understand the role of TL (and the point at which they may act) in the pathological progression in colorectal neoplasia.

Our analysis is an important addition to the literature, because it is the first study to report a statistically significant association of TL with serrated polyps, suggesting that telomeres may play an important role along the entire serrated pathway. There was also a suggestion of increased risk, particularly, for SSA/Ps. SSA/Ps are newly-recognized precursors to CRC [16]; thus, this finding may provide valuable insights into the underlying mechanisms for cancer progression within the serrated pathway. Further work is warranted to determine whether TL can serve as a reliable biomarker for such a neoplastic progression.

Our study is larger than most other studies of colorectal polyps and TL, but it is nonetheless limited by sample size, particularly as colorectal polyp cases were further divided into smaller subgroups based on lesion severity. However, this enabled us to look at differences within sub-classes of colorectal polyps. Also, misclassification of disease status in some cases and controls is possible, particularly with respect to the harder to visualize SSA/Ps. However, such misclassification would be non-differential and would bias estimates towards the null. Hence, our reported positive association with serrated polyps is conservative. Finally, although we have controlled for major potential confounders, including age, sex, smoking, body mass index, and inflammation, we cannot exclude the possibility of residual confounding by measured and unmeasured risk factors. Strengths of our study include the high-quality and detailed characterization of colorectal polyp cases and controls using colonoscopy and standardized pathology review, which enabled us to evaluate the relationship between short telomeres and various polyp subtypes. Additionally, to our knowledge, this is the first study to report associations between short telomeres and advanced polyps within the serrated pathway.

In conclusion, short telomeres were associated with an increased risk of colorectal polyps in both the adenoma-carcinoma and serrated pathways, although the increased risk was statistically significant only for serrated polyps. Among individuals with serrated polyps, the risk associated with short telomeres appeared stronger, but not statistically significant, for those with SSA/Ps. Future prospective studies are needed to define the temporal sequence between TL and these high risk lesions, and to elucidate the role of telomeres as a biomarker for CRC risk stratification.