Genetic Risk Score for Telomere Length Predictive of Lung Adenocarcinoma

Newswise — An unprecedented large study led by Brandon Pierce, PhD with Jennifer A. Doherty, PhD, provides compelling evidence that long telomere length increases the risk of lung adenocarcinoma. Their paper, “Genetic Determinants of Telomere Length and Risks of Common Cancers: A Mendelian Randomization Study,” published in Human Molecular Genetics, details an unusual approach to predict telomere length based on genetic factors, rather than actual length, which is subject to wear and tear.

“The innovation here includes the Mendelian randomization approach, which is not prone to biases from lifestyle or treatment-related factors, the tremendous size of the study, and the examination of associations across the most common types of cancer,” said Doherty, an epidemiologist at Dartmouth’s Norris Cotton Cancer Center. “Our study adds genetic evidence to a growing body of literature that points to a causal association between long telomere length and lung adenocarcinoma.”

Telomeres cap the ends of chromosomes and protect them from degradation and genomic instability. Some have likened telomeres to the plastic caps that protect the ends of shoelaces. Variants in the gene that helps to maintain telomeres are associated with numerous cancer types, but the associations are complicated. For instance, different variants appear to be associated with different cancer types. With some variants, it is even more complicated because they are associated with both increased risk of some cancer types and decreased risk of others.

The study, which involved an international collaboration of investigators, was funded by the National Cancer Institute sponsored Genetic Associations and Mechanisms in Oncology Network, known as GAME-ON, to examine whether genetic factors that predict telomere length are associated with five of the most common cancers and their sub-types. By using a Mendelian randomization approach, they developed a genetic risk scoring system that represented telomere length, allowing examination of telomere length and cancer risk that were not prone to biases from lifestyle or treatment-related factors.

The investigators found that a genetic risk score for long telomere length was associated with increased risk of lung adenocarcinoma, but not squamous cell lung cancer, prostate, breast, ovarian, or colorectal cancers.

“Of particular importance is our use of the Mendelian randomization approach, which has provided us with an important angle to examine telomere length without physically measuring it,” explained Pierce. “And 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.”

Looking forward, new studies will examine the genetic risk score for telomere length in additional populations, and evaluate whether some groups based on age, gender, smoking history, and other factors may be at particularly increased risk. The long term goal is to accurately predict and prevent lung adenocarcinoma.

This study represents a large-scale collaboration through the GAME-ON network, which systematically combined data from 45 genome-wide association studies of various cancer types. These data are being used by a multidisciplinary group of researchers to examine many different hypotheses across cancer types.

Brandon Pierce is Assistant Professor of Epidemiology at the Department of Public Health Sciences, University of Chicago.

Jennifer A. Doherty is Assistant Professor of Epidemiology at Dartmouth’s Geisel School of Medicine. Her work in cancer is facilitated by Dartmouth’s Norris Cotton Cancer Center where she is a member of the Cancer Epidemiology Research Program.

Funding for this study came from the National Cancer Institute sponsored Genetic Associations and Mechanisms in Oncology Network, known as GAME-ON, and other grants to individual investigators.

About Norris Cotton Cancer Center at Dartmouth-Hitchcock Norris Cotton Cancer Center combines advanced cancer research at Dartmouth and the Geisel School of Medicine with patient-centered cancer care provided at Dartmouth-Hitchcock Medical Center in Lebanon, NH, at Dartmouth-Hitchcock regional locations in Manchester, Nashua, and Keene, NH, and St. Johnsbury, VT, and at 12 partner hospitals throughout New Hampshire and Vermont. It is one of 45 centers nationwide to earn the National Cancer Institute’s “Comprehensive Cancer Center” designation. Learn more about Norris Cotton Cancer Center research, programs, and clinical trials online at cancer.dartmouth.edu.