Telomere Length Genes Predict Lung Adenocarcinoma Risk

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Genes associated with long telomere length increase the risk of pulmonary adenocarcinoma, and possibly prostate cancer, according to authors of a large international study published in Human Molecular Genetics.¹

“This work provides compelling evidence that the traditional view that ‘short telomeres are bad for health’ does not hold for some cancer types, lung adenocarcinoma in particular,” added lead study author Brandon Pierce, PhD, Assistant Professor of Epidemiology at the Department of Public Health Sciences, University of Chicago.

Telomeres are often likened to aglets – the plastic caps that protect the tips of shoelaces -- because they cap the ends of chromosomes in comparable fashion, protecting them from damage and eventually resulting genomic instability. Telomere damage and shortening leaves chromosomes vulnerable to ensuing genomic instability, which normally triggers cell senescence and apoptosis.

Numerous previous studies of physically measured telomeres have yielded inconsistent relationships between telomere length and cancer risks. Such inconsistencies appear to be due, at least in part, to lifestyle factors like tobacco smoking or night shift work, which are associated with hastened telomere destruction, and the use of postdiagnostic and post-treatment telomere measurement in much of the published research literature.

To determine whether or not intrinsic telomere length, before such environmental damage occurs, predicts cancer risks, the researchers looked at variants in nine single-nucleotide polymorphisms (SNPs) associated with telomere length, and the risk of breast, lung, colorectal, ovarian and prostate cancers, with data from the National Cancer Institute (NCI)’s Genetic Associations and Mechanisms in Oncology (GAME-ON) initiative.² The study analyses involved GAME-ON data from 51,725 patients with cancer diagnoses and 62,035 controls.

The authors devised a long telomere length multi-SNP genetic score reflecting variation in the nine telomere length-associated SNPs. They then statistically analyzed SNP-specific associations with cancer risks.

“Because genotype-phenotype associations are not vulnerable to biases caused by reverse causation or confounding by environment, the Mendelian randomization approach used in this study is an attractive approach for estimating relationships between telomere length and cancer risk,” the coauthors reported.

The multi-SNP genetic telomere length score correlated significantly with an increased risk of lung adenocarcinoma (P = 6.3 x 10^-15), even after removal of a SNP found in a known lung cancer susceptibility region (TERT-CLPTM1L).

“We did not observe an association between the multi-SNP score and risk of breast, colorectal or ovarian cancer (including subtypes),” the coauthors reported.

They cautioned that the Mendelian randomization approach assumes that the SNPs included in the analysis do not exert pleiotropic effects on cancer risk through mechanisms other than telomere length. The analysis also assumed that associations between telomere length and cancer risk are linear; “the existence of a nonlinear (e.g., U-shaped) association may limit our ability to detect an association,” they noted.

The multi-SNP score exhibited a trend toward predicting prostate cancers, as well, but that trend fell short of statistical significance (P = .06), the authors noted. However, after excluding some SNPs from the multi-SNP score based on “potential violation of the Mendelian randomization assumptions,” the score did significantly increase prostate cancer risk. Few studies of telomere length and prostate cancer risk have been published, the coauthors noted – and those prior studies did not report statistically significant associations.

“Our study adds genetic evidence to a growing body of literature that points to a causal association between long telomere length and lung adenocarcinoma,” reported Jennifer A. Doherty, PhD, an epidemiologist at Dartmouth’s Norris Cotton Cancer Center and Assistant Professor of Epidemiology at Dartmouth’s Geisel School of Medicine.³

“The multi-SNP score for telomere length should be further investigated as a predictor of adenocarcinoma of the lung, a common lung cancer subtype in both smokers and nonsmokers,” Doherty and her coauthors reported. “Future research needs to be undertaken to determine the value of telomeres as a novel risk measure or a modifiable pharmacological target, with the long-term goal of improving cancer prediction and prevention.”

The study was funded by the NCI’s GAME-ON initiative, US National Institute on Aging, The Wellcome Trust, and individual participating investigators’ research grants.

References:

• Chenan Z, Doherty JA, Burgess S, et al. (2015). Genetic determinants of telomere length and risk of common cancers: a Mendelian randomization study. Human Molecular Genetics, Sep 15;24(18):5356-66.
• The National Cancer Institute Epidemiology and Genomics Research Program. (2015). Genetic Associations and Mechanisms in Oncology (GAME-ON): A Network of Consortia for Post-Genome Wide Association (Post-GWA) Research.
• Dartmouth-Hitchcock Norris Cotton Cancer Center. (2015). Research Finds Telomere Length Predictive of Lung Adenocarcinoma.