Mendelian Randomization and mediation analysis of leukocyte telomere length and risk of lung and head and neck cancers (original) (raw)
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Cancer Research, 2016
Background: Telomere length (TL) is a predictor of lung cancer risk, but the direction of this association differs between and prospective and case-control studies. This discrepancy may be attributed to reverse causation in the latter, due to disease-related changes in TL that is measured after diagnosis or treatment. To overcome these limitations and characterize the relationship between TL and lung cancer risk we carried out observational and mediation analyses, and a 2-stage Mendelian Randomization (MR) analysis, where we developed novel genetic instruments for TL and tested the association with lung cancer using 20 OncoArray studies in the Transdisciplinary Research in Cancer of the Lung group of the International Lung Cancer Consortium. Methods: The observational analysis examined TL measured using qPCR in 1128 cases and 928 controls. Odds ratios (OR) for TL were adjusted for age, sex and cigarette pack-years. Mediation analysis was used to estimate the% of the lung cancer asso...
Genetic determinants of telomere length and risk of common cancers: a Mendelian randomization study
Epidemiological studies have reported inconsistent associations between telomere length (TL) and risk for various cancers. These inconsistencies are likely attributable, in part, to biases that arise due to postdiagnostic and post-treatment TL measurement. To avoid such biases, we used a Mendelian randomization approach and estimated associations between nine TL-associated SNPs and risk for five common cancer types (breast, lung, colorectal, ovarian and prostate cancer, including subtypes) using data on 51,725 cases and 62,035 controls. We then 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. The long TL genetic score was significantly associated with increased risk of lung adenocarcinoma (P=6.3x10 -15 ), even after exclusion of a SNP residing in a known lung cancer susceptibility region (TERT-CLPTM1L) P=6.6x10 -6 ). Under Mendelian randomization assumptions, the association estimate (odds ratio (OR)=2.78) is interpreted as the OR for lung adenocarcinoma corresponding to a 1000 base pair increase in TL. The weighted TL SNP score was not associated with other cancer types or subtypes. 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. Under Mendelian randomization assumptions, our finding suggests that longer TL increases lung adenocarcinoma risk. 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. at University of Cambridge on July 6, 2015 http://hmg.oxfordjournals.org/ Downloaded from at University of Cambridge on July 6, 2015 http://hmg.oxfordjournals.org/ Downloaded from 6 undertook a comprehensive examination of associations between genetic determinants of TL and cancer risk.
Is Leukocyte Telomere Length Related with Lung Cancer Risk?: A Meta-Analysis
Iranian biomedical journal, 2016
Epidemiological studies have probed the correlation between telomere length and the risk of lung cancer, but their findings are inconsistent in this regard. The present meta-analysis study has been carried out to demonstrate the association between relative telomere length in peripheral blood leukocytes and the risk of lung cancer using an established Q-PCR technique. A systematic search was carried out using PubMed, EMBASE, and ISI before 2015. A total of 2925 cases of lung cancer and 2931 controls from 9 studies were employed to probe the relationship between lung cancer and telomere length .ORs were used at 95% CI. Random-effects models were used to investigate this relationship based on the heterogeneity test. Heterogeneity among studies was analyzed employing subgroup analysis based on type studies and the year of publication. Random-effects meta-analysis revealed that patients with lung cancer were expected to have shorter telomere length than the control (1.13, 95% CI: 0.82-1...
JAMA oncology, 2017
The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation. To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases. Genomewide association studies (GWAS) published up to January 15, 2015. GWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available. Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population. Odds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviatio...
International journal of cancer. Journal international du cancer, 2014
Recent evidence from several relatively small nested case-control studies in prospective cohorts shows an association between longer telomere length measured phenotypically in peripheral white blood cell (WBC) DNA and increased lung cancer risk. We sought to further explore this relationship by examining a panel of seven telomere-length associated genetic variants in a large study of 5,457 never-smoking female Asian lung cancer cases and 4,493 never-smoking female Asian controls using data from a previously reported genome-wide association study. Using a group of 1,536 individuals with phenotypically measured telomere length in WBCs in the prospective Shanghai Women's Health study, we demonstrated the utility of a genetic risk score (GRS) of seven telomere-length associated variants to predict telomere length in an Asian population. We then found that GRSs used as instrumental variables to predict longer telomere length were associated with increased lung cancer risk (OR = 1.51 ...
Telomere Dysfunction: A Potential Cancer Predisposition Factor
JNCI Journal of the National Cancer Institute, 2003
Background: Genetic instability associated with telomere dysfunction (i.e., short telomeres) is an early event in tumorigenesis. We investigated the association between telomere length and cancer risk in four ongoing case-control studies. Methods: All studies had equal numbers of case patients and matched control subjects (92 for head and neck cancer, 135 for bladder cancer, 54 for lung cancer, and 32 for renal cell carcinoma). Telomere length was measured in peripheral blood lymphocytes from study participants. Genetic instability was assessed with the comet assay. Patient and disease characteristics were collected and analyzed for associations with risk for these cancers. All statistical tests were twosided. Results: Telomeres were statistically significantly shorter in patients with head and neck cancer (6.5 kilobases [kb]) than in control subjects (7.4 kb) (difference = 0.9 kb, 95% confidence interval [CI] = 0.5 to 1.2 kb; P<.001). Nine percent of patients with head and neck cancer were in the longest quartile of telomere length, whereas 59% were in the shortest quartile. Similar patterns were observed for lung, renal cell, and bladder cancer. When subjects were categorized into telomere length quartiles defined by the distribution in control subjects, the following inverse relationship between telomere length and cancer risk was observed: adjusted odds ratios [ORs] for decreasing quartiles = 0.84 (95% CI = 0.36 to 1.97), 1.77 (95% CI = 0.72 to 4.36), and 5.11 (95% CI = 1.90 to 13.77). In stratified analysis, we found a suggestive greater-than-additive interaction between smoking status and telomere length: for ever smokers with short telomeres, OR = 25.05 (95% CI = 6.91 to 90.73); for never smokers with short telomeres, OR = 6.18 (95% CI = 1.72 to 22.13); and for ever smokers with long telomeres, OR = 6.49 (95% CI = 1.54 to 27.38). Telomere length was statistically significantly and inversely associated with baseline and mutagen-induced genetic instability. Conclusion: Short telomeres appear to be associated with increased risks for human bladder, head and neck, lung, and renal cell cancers.
Telomere structure and maintenance gene variants and risk of five cancer types
International journal of cancer, 2016
Telomeres cap chromosome ends, protecting them from degradation, double-strand breaks, and end-to-end fusions. Telomeres are maintained by telomerase, a reverse transcriptase encoded by TERT, and an RNA template encoded by TERC. Loci in the TERT and adjoining CLPTM1L region are associated with risk of multiple cancers. We therefore investigated associations between variants in 22 telomere structure and maintenance gene regions and colorectal, breast, prostate, ovarian, and lung cancer risk. We performed subset-based meta-analyses of 204,993 directly-measured and imputed SNPs among 61,851 cancer cases and 74,457 controls of European descent. Independent associations for SNP minor alleles were identified using sequential conditional analysis (with gene-level P-value cutoffs ≤3.08x10(-5) ). Of the thirteen independent SNPs observed to be associated with cancer risk, novel findings were observed for seven loci. Across the TERT-CLPTML1 region, rs12655062 was associated positively with pr...
Aging Cell, 2009
Telomeres consist of nucleotide repeats and a protein complex at chromosome ends that are essential to maintaining chromosomal integrity. Several studies have suggested that subjects with shorter telomeres are at increased risk of bladder and lung cancer. In comparison to normal tissues, telomeres are shorter in high-grade intraepithelial neoplasia and prostate cancer. We examined prostate cancer risk associated with relative telomere length as determined by quantitative PCR on pre-diagnostic buffy coat DNA isolated from 612 advanced prostate cancer cases and 1049 agematched, cancer-free controls from the PLCO Cancer Screening Trial. Telomere length was analyzed as both a continuous and a categorical variable with adjustment for potential confounders. Statistically significant inverse correlations between telomere length, age and smoking status were observed in cases and controls. Telomere length was not associated with prostate cancer risk (at the median, OR = 0.85, 95% CI 0.67, 1.08); associations were similar when telomere length was evaluated as a continuous variable or by quartiles. The relationships between telomere length and inflammation-related factors, diet, exercise, body mass index, and other lifestyle variables were explored since many of these have previously been associated with shorter telomeres. Healthy lifestyle factors (i.e., lower BMI, more exercise, tobacco abstinence, diets high in fruit and vegetables) tended to be associated with greater telomere length. This study found no statistically significant association between leukocyte telomere length and advanced prostate cancer risk. However, correlations of telomere length with healthy lifestyles were noted, suggesting the role of these factors in telomere biology maintenance and potentially impacting overall health status.
International journal of cancer, 2018
Telomere shortening occurs as an early event in tumorigenesis. The TERT-CLPTM1L locus associates with nasopharyngeal carcinoma (NPC) risk. It remains unknown if leukocyte telomere length (LTL) associates with NPC risk and survival. The relative LTL (rLTL) was measured by quantitative-PCR in 2996 individuals comprised of 1284 NPC cases and 1712 matched controls. The odds ratio (OR) and 95% confidence intervals (CI) were calculated by logistic regression. The hazard ratio (HR) and 95% CI were calculated by Cox regression for survival analysis with rLTL and other clinical parameters in 1243 NPC with a minimum follow-up period of 25 months. NPC patients had significantly shorter telomere length than controls. Shorter rLTL significantly associated with increased NPC risk, when the individuals were dichotomized into long and short telomeres based on median-split rLTL in the control group (OR=2.317; 95% CI=1.989-2.700, p=4.10x10 ). We observed a significant dose-response association (p =3....