Telomere shortening results in chromosomal instability which, in the absence of normal cellular senescence processes, can lead to cancer development. Patients with germline defects in telomere biology, such as those with DC, have a very high risk of cancer (9
). Most somatic cancer cells have significant aberrations in telomere biology. Therefore, it is biologically plausible that individuals with short telomeres, even if they are not as short as in DC, might be at increased risk of cancer compared to individuals with longer telomeres. This hypothesis formed the basis for the association studies of cancer and TL described in our report.
Studies on bladder, esophageal, gastric, head and neck, ovarian, renal, and overall incident cancer found that shorter telomeres were significantly associated with these cancers. Findings from studies on non-Hodgkin lymphoma, breast, lung and colorectal cancer were inconsistent. Single studies on endometrial, prostate, and skin cancers found no associations. Our meta-analysis showed a statistically significant positive OR and therefore suggests an association between short TL and cancer in the studies evaluated. This estimate, however, is heavily weighted by the larger studies and cancer types on which most studies were conducted. Results from very small studies and in cancer types, for which only one or two reports (e.g., head and neck, ovarian cancer) have been conducted so far, need to be interpreted with caution. Thus, these results may not be representative of all cancer types.
This meta-analysis accounted for the variability in TL measurement methods between studies. Most studies used Q-PCR, a high-throughput method which is suitable for large epidemiologic studies. While the CVs have improved significantly since its development, the CVs in the reviewed reports are highly variable. In addition, only one report published an ICC which is more suitable to assess repeatability of an assay. The reproducibility between laboratories, the effects of DNA extraction, and DNA storage need to be addressed in future studies. Methodologic studies of TL measured by terminal restriction fragment (TRF) analysis by Southern blot, Q-PCR, Q-FISH, and correlations with single TL measurement are also needed to assess the evidence from different studies. These details should be reported in future TL association studies.
Our findings are intriguing, but several questions remain to be answered: 1.) What is the role of TL in surrogate tissues in the etiology of specific cancers? 2.) Could reverse causation bias explain the discrepant findings in studies with variable findings in the same cancer type? and 3.) How is telomere shortening related to or influenced by common cancer risk factors (e.g., smoking or inflammation)?
Surrogate tissue TL may be a marker of genetic risk and/or environmental exposures that are related to cancer etiology. A limited number of intra-individual TL studies suggest that TL differs between tissues, but that it is correlated within an individual (36
). Thus measuring TL within a surrogate tissue, such as blood or buccal cells may aid in understanding TL in other tissues. However, it is possible that variability in surrogate tissue TL, and the potential direct exposure of that tissue to carcinogens (e.g
., buccal cell exposure to cigarette smoke) could explain discrepant results in some of the studies described. For example, it is not known if there are differential effects of smoking on TL in oral or lung tissues, which are directly exposed to cigarette smoke, compared to tissues without direct contact, such as blood cells.
The majority of the published studies reviewed were case-control studies which obtained DNA from the cases after cancer diagnosis. This could result in reverse causation bias, where changes in surrogate tissue TL could be a consequence of the presence of malignant disease rather than an etiologic marker. Studies of incident prostate, skin, colon, and breast cancers (13
), in which samples were collected months or years prior to cancer diagnosis, did not find significant evidence for associations between TL and cancer risk.
The majority of the reviewed studies do not give information on administration of chemotherapy or radiation therapy prior to DNA collection. There is theoretical consideration and empirical data that both therapeutic modalities shorten telomeres (50
). Only two small studies of the reviewed reports [ovarian cancer, (24
), and breast cancer, (14
)] commented on treatment. They, however, did not find a difference between cases who received chemotherapy prior to sample collection and those who did not. Comparison of prospectively collected samples to samples collected at the time of enrollment after breast or colon cancer diagnosis suggested that telomere shortening occurred primarily after diagnosis (25
). Additional prospective cohort studies, with collection of serial samples, and inclusion of treatment data are required to better understand the differences in these findings.
Studies which assess potential interactions between known cancer risk factors on TL and cancer risk are important to understanding these associations. Data suggesting that other risk factors, such as obesity, other hormones, even stress or lifestyle, influence TL and risk of cancer have been discussed elsewhere (53
). Cancer types with no or inconsistent associations with TL include breast and prostate cancers. These cancer types are predominantly influenced by hormones. The role of cigarette smoke or inflammation in the development of these cancers is either minimal or ill-defined (55
). Notably, estrogen has anti-inflammatory and antioxidant activities which may have protective properties against the development of cancer. In addition, estrogen can stimulate telomerase (56
). This might explain some discrepancy in the breast cancer reports in pre- and postmenopausal patients.
All cancers found to date to be associated with short TL have either an inflammatory component (e.g
., bladder and gastric cancers) and/or are strongly associated with a known carcinogen, such as smoking (e.g
., bladder and lung cancers). Telomere shortening can occur as a result of oxidative stress (57
). The reactive oxygen species present in cigarette smoke may explain, in part, the studies suggesting an association between the cumulative lifetime exposure to cigarette smoke and more rapid telomere shortening (58
). Studies with detailed smoking exposure data, telomere length, and cancer are needed to better understand this potential interaction.
Chronic inflammation is a known risk factor for some cancers (e.g
., esophageal, bladder, and gastric cancer) and is also associated with high granulocyte turnover (60
). Since telomeres shorten with each cell division, this may result in shorter granulocyte telomeres causing a reduction of the reported TL of DNA from total leukocytes. Several cytokines may activate telomerase which could, in part, compensate for telomeric loss (61
). Ulcerative colitis is another example of the complex interplay between inflammation, cancer, and telomere attrition. In this chronic inflammatory condition, individuals are at increased risk of colon cancer; patients with higher rates of chromosomal instability and shorter telomeres are at greater risk of progression to colon cancer (63
). It is possible that individuals who are most susceptible to smoking and/or inflammation-related cancers may also be susceptible to more rapid telomere attrition due to a combination of genetics and environmental exposures.
In summary, our meta-analysis showed suggestive evidence for an association between short TL and overall cancer, but this effect may be driven by stronger effects in specific cancers, the presence of reverse causation bias, and/or the potential effect of prior cancer therapy in case-control studies. The ORs for retrospective studies were much higher than for prospective studies (2.9 versus 1.16) which is consistent with the presence of reverse causation bias and possible contribution of cancer therapy prior to sample collection. Notably, the sub-analysis on breast cancers showed no significant association with TL. Heterogeneity between all studies was substantial. Some studies were small and the number of studies for each cancer type is still limited. Conclusions for cancer types in which only or very few studies have been conducted have to be interpreted with caution. For many cancers, the association between TL and risk of cancer has not yet been investigated. It is also biologically conceivable that analyzing average TL over all chromosomes combined might blur effects since the shortest telomere in a cell may be the most critical. Future studies of chromosome specific TL will be required to better understand this aspect. Large, prospective studies of specific cancer types which evaluate TL before and after cancer diagnosis with detailed information on treatment modalities will also be required to better understand the role of surrogate tissue TL and cancer risk.