Dataset Information

Mendelian Randomization and mediation analysis of leukocyte telomere length and risk of lung and head and neck cancers.

ABSTRACT:

Background

Evidence from observational studies of telomere length (TL) has been conflicting regarding its direction of association with cancer risk. We investigated the causal relevance of TL for lung and head and neck cancers using Mendelian Randomization (MR) and mediation analyses.

Methods

We developed a novel genetic instrument for TL in chromosome 5p15.33, using variants identified through deep-sequencing, that were genotyped in 2051 cancer-free subjects. Next, we conducted an MR analysis of lung (16 396 cases, 13 013 controls) and head and neck cancer (4415 cases, 5013 controls) using eight genetic instruments for TL. Lastly, the 5p15.33 instrument and distinct 5p15.33 lung cancer risk loci were evaluated using two-sample mediation analysis, to quantify their direct and indirect, telomere-mediated, effects.

Results

The multi-allelic 5p15.33 instrument explained 1.49-2.00% of TL variation in our data (p?=?2.6?×?10-9). The MR analysis estimated that a 1000 base-pair increase in TL increases risk of lung cancer [odds ratio (OR)?=?1.41, 95% confidence interval (CI): 1.20-1.65] and lung adenocarcinoma (OR?=?1.92, 95% CI: 1.51-2.22), but not squamous lung carcinoma (OR?=?1.04, 95% CI: 0.83-1.29) or head and neck cancers (OR?=?0.90, 95% CI: 0.70-1.05). Mediation analysis of the 5p15.33 instrument indicated an absence of direct effects on lung cancer risk (OR?=?1.00, 95% CI: 0.95-1.04). Analysis of distinct 5p15.33 susceptibility variants estimated that TL mediates up to 40% of the observed associations with lung cancer risk.

Conclusions

Our findings support a causal role for long telomeres in lung cancer aetiology, particularly for adenocarcinoma, and demonstrate that telomere maintenance partially mediates the lung cancer susceptibility conferred by 5p15.33 loci.

SUBMITTER: Kachuri L

PROVIDER: S-EPMC6659464 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Publications

Mendelian Randomization and mediation analysis of leukocyte telomere length and risk of lung and head and neck cancers.

Kachuri Linda L Saarela Olli O Bojesen Stig Egil SE Davey Smith George G Liu Geoffrey G Landi Maria Teresa MT Caporaso Neil E NE Christiani David C DC Johansson Mattias M Panico Salvatore S Overvad Kim K Trichopoulou Antonia A Vineis Paolo P Scelo Ghislaine G Zaridze David D Wu Xifeng X Albanes Demetrius D Diergaarde Brenda B Lagiou Pagona P Macfarlane Gary J GJ Aldrich Melinda C MC Tardón Adonina A Rennert Gad G Olshan Andrew F AF Weissler Mark C MC Chen Chu C Goodman Gary E GE Doherty Jennifer A JA Ness Andrew R AR Bickeböller Heike H Wichmann H-Erich HE Risch Angela A Field John K JK Teare M Dawn MD Kiemeney Lambertus A LA van der Heijden Erik H F M EHFM Carroll June C JC Haugen Aage A Zienolddiny Shanbeh S Skaug Vidar V Wünsch-Filho Victor V Tajara Eloiza H EH Ayoub Moysés Raquel R Daumas Nunes Fabio F Lam Stephen S Eluf-Neto Jose J Lacko Martin M Peters Wilbert H M WHM Le Marchand Loïc L Duell Eric J EJ Andrew Angeline S AS Franceschi Silvia S Schabath Matthew B MB Manjer Jonas J Arnold Susanne S Lazarus Philip P Mukeriya Anush A Swiatkowska Beata B Janout Vladimir V Holcatova Ivana I Stojsic Jelena J Mates Dana D Lissowska Jolanta J Boccia Stefania S Lesseur Corina C Zong Xuchen X McKay James D JD Brennan Paul P Amos Christopher I CI Hung Rayjean J RJ

International journal of epidemiology 20190601 3

<h4>Background</h4>Evidence from observational studies of telomere length (TL) has been conflicting regarding its direction of association with cancer risk. We investigated the causal relevance of TL for lung and head and neck cancers using Mendelian Randomization (MR) and mediation analyses.<h4>Methods</h4>We developed a novel genetic instrument for TL in chromosome 5p15.33, using variants identified through deep-sequencing, that were genotyped in 2051 cancer-free subjects. Next, we conducted a ...[more]

PMID: 30059977

Similar Datasets

Project description:Background: Telomere shortening is a hallmark of cellular senescence. However, telomere length (TL)-related cellular senescence has varying effects in different cancers, resulting in a paradoxical relationship between senescence and cancer. Therefore, we used observational epidemiological studies to investigate the association between TL and skin cancer and aging, and to explore whether such a paradoxical relationship exists in skin tissue. Methods: This study employed two-sample Mendelian randomization (MR) to analyze the causal relationship between TL and skin cancer [melanoma and non-melanoma skin cancers (NMSCs)] and aging. We studied single nucleotide polymorphisms (SNPs) obtained from pooled data belonging to genome-wide association studies (GWAS) in the literature and biobanks. Quality control was performed using pleiotropy, heterogeneity, and sensitivity analyses. Results: We used five algorithms to analyze the causal relationship between TL and skin aging, melanoma, and NMSCs, and obtained consistent results. TL shortening reduced NMSC and melanoma susceptibility risk with specific odds ratios (ORs) of 1.0344 [95% confidence interval (CI): 1.0168–1.0524, p = 0.01] and 1.0127 (95% CI: 1.0046–1.0209, p = 6.36E-07), respectively. Conversely, TL shortening was validated to increase the odds of skin aging (OR = 0.96, 95% CI: 0.9332–0.9956, p = 0.03). Moreover, the MR-Egger, maximum likelihood, and inverse variance weighted (IVW) methods found significant heterogeneity among instrumental variable (IV) estimates (identified as MR-Egger skin aging Q = 76.72, p = 1.36E-04; melanoma Q = 97.10, p = 1.62E-07; NMSCsQ = 82.02, p = 1.90E-05). The leave-one-out analysis also showed that the SNP sensitivity was robust to each result. Conclusion: This study found that TL shortening may promote skin aging development and reduce the risk of cutaneous melanoma and NMSCs. The results provide a reference for future research on the causal relationship between skin aging and cancer in clinical practice.

Dataset Information

Mendelian Randomization and mediation analysis of leukocyte telomere length and risk of lung and head and neck cancers.

Background

Methods

Results

Conclusions

Publications

Mendelian Randomization and mediation analysis of leukocyte telomere length and risk of lung and head and neck cancers.

Similar Datasets

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