As their ends erode bit by bit, telomeres become ever stumpier, leaving the chromosomes they cap ever more vulnerable, bringing cell death ever closer. To delay cell death—and extend your own life—you might wish for very long telomeres. Well, be careful what you wish for. According to a new study, long telomeres are associated with an increased risk of lung adenocarcinoma.

The new study, led by scientists from the University of Chicago, took on the difficult task of assessing whether telomere length affects the risk of various cancers, including breast, colorectal, lung, ovarian, and prostate cancer. Telomere length, it turns out, can be an ambiguous measure. It can vary greatly due to factors such as age, lifestyle, and cancer progression.

The problem of telomere length, the scientists decided, could be avoided if they didn’t even try to measure telomeres—not directly, anyway. Instead, the scientists used Mendelian randomization, a method which estimates telomere length based on genetic factors. The scientists 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.

Using genome data from 51,725 cancer cases and 62,035 controls through the GAME-ON (Genetic Associations and Mechanisms in Oncology) network, the scientists compared telomere lengths with the risk of developing various types of cancer.

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 (TL). This finding appeared July 29 in Human Molecular Genetics, in an article entitled, “Genetic determinants of telomere length and risk of common cancers: a Mendelian randomization study.”

“We used an inverse-variance weighted average of the SNP-specific associations to estimate the association between a genetic score representing long TL and cancer risk,” wrote the authors. “The long TL genetic score was significantly associated with increased risk of lung adenocarcinoma, even after exclusion of a SNP residing in a known lung cancer susceptibility region (TERT-CLPTM1L).”

The authors added that the weighted TL SNP score was not associated with other cancer types of subtypes. Aside from lung cancer, only prostate cancer risk showed a modest positive association with long telomeres.

“Our work provides compelling evidence of a relationship between long telomeres and increased risk for lung adenocarcinoma,” said study leader Brandon Pierce, Ph.D., assistant professor of public health sciences at the University of Chicago. “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.”

The scientists suggested that long telomeres could 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 role of telomeres in cancer biology, Dr. Pierce and colleagues warn that while Mendelian randomization produces estimates of causal relationships, estimates could be biased if the genetic variants measured in the study affect cancer risk and telomere length independently.

“Our finding that genetic determinants of long TL increase lung adenocarcinoma risk avoids issues with reverse causality and residual confounding that arise in observational studies of TL and disease risk,” the authors noted Human Molecular Genetics. “However, caution regarding this causal interpretation is warranted in light of the potential issue of pleiotropy, and a more general interpretation is that SNPs influencing telomere biology are also implicated in lung adenocarcinoma risk.”








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