The protective caps on DNA are called telomeres. Shortened telomeres have been implicated in aging and cardiovascular diseases, but their relationship with cancer risk is still unclear.
Scientists wanted to see if there could be a link between telomere length and risk for five common cancers. They found that having a genetic predisposition for long—not short—telomeres is associated with one of the five cancers: lung adenocarcinoma.
The findings are published in Human Molecular Genetics.
“The prevailing hypothesis has been that short telomeres are bad for health, but it appears that this does not necessarily translate to some types of cancer,” says study leader Brandon Pierce, assistant professor of public health sciences at the University of Chicago.
How telomeres get shorter
A portion of the telomere DNA is lost during cell division. This leads to telomere shortening over time, which has been thought of as a time-delay “fuse” that can trigger cell death or genomic instability.
Because telomeres can vary greatly due to factors such as age, lifestyle, and cancer progression, efforts to study the direct associations between cancer risk and telomere length have been difficult.
To address this issue, Pierce and colleagues used Mendelian randomization, a method that calculates telomere length based on genetic factors. They created a score based on a combination of genetic variants identified by prior genome-wide association studies as being associated with telomere length.
Since genetics remain unchanged even as telomeres physically shorten, this measurement allowed for unbiased comparisons to cancer risk.
5 common cancers
Using genome data from more than 50,000 cancer cases and 60,000 controls through the GAME-ON (Genetic Associations and Mechanisms in Oncology) network, the team compared telomere lengths with the risk of developing breast, lung, colorectal, ovarian, and prostate cancers, including subtypes.
They found that longer telomeres were significantly associated with increased risk for lung cancer—specifically lung adenocarcinoma—which more than doubled in risk for every 1,000 base pair increase in telomere length.
Surprisingly, the researchers found no associations between shortened telomeres and cancer risk. Aside from lung cancer, only prostate cancer risk showed a modest positive association with long telomeres.
“Mendelian randomization is an important tool that allows us to examine telomere length without the problematic biases that come with physically measuring it,” says study author Chenan Zhang, graduate student in public health sciences. “The positive association between telomere length and lung adenocarcinoma should be further investigated with the long term goal of improving prediction and prevention of this common cancer subtype.”
The team suggests a potential explanation for this observation is that long telomeres enable more rounds of cell division than short telomeres, which could allow cells to live longer and have more opportunities to accumulate carcinogenic mutations.
While their results shed light on the unclear role of telomeres in cancer biology, Pierce and his colleagues warn that Mendelian randomization produces estimates of causal relationships, but the estimates could be biased if the genetic variants measured in the study affect cancer risk and telomere length independently.
However, the method holds significant advantages and has successfully been used to investigate associations such as those between heart disease and cholesterol types. The team is now examining telomere length in additional populations to evaluate whether some groups based on age, gender, smoking history, and other factors may be at additional increased risk.
“The complex relationship between telomeres and cancer risk is one that we need to further understand,” Pierce says. “This study gives us an estimate of a causal relationship that could serve as a guidepost for the development of interventions in the future.”
The Genetic Associations and Mechanisms in Oncology Network, Genetics and Epidemiology of Colorectal Cancer Consortium, the National Cancer Institute, the National Institute on Aging, the Cancer Research Foundation, the Wellcome Trust, and the National Health and Medical Research Council funded the study.
Source: University of Chicago