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Abstract
Background:
Tobacco exposure causes 8 of 10 lung cancers, and identifying additional risk factors is challenging due to confounding introduced by smoking in traditional observational studies.
Materials and Methods:
We used Mendelian randomization (MR) to screen 207 metabolites for their role in lung cancer predisposition using independent genome-wide association studies (GWAS) of blood metabolite levels (n = 7,824) and lung cancer risk (n = 29,266 cases/56,450 controls). A nested case–control study (656 cases and 1,296 matched controls) was subsequently performed using prediagnostic blood samples to validate MR association with lung cancer incidence data from population-based cohorts (EPIC and NSHDS).
Results:
An MR-based scan of 207 circulating metabolites for lung cancer risk identified that blood isovalerylcarnitine (IVC) was associated with a decreased odds of lung cancer after accounting for multiple testing (log10-OR = 0.43; 95% CI, 0.29–0.63). Molar measurement of IVC in prediagnostic blood found similar results (log10-OR = 0.39; 95% CI, 0.21–0.72). Results were consistent across lung cancer subtypes.
Conclusions:
Independent lines of evidence support an inverse association of elevated circulating IVC with lung cancer risk through a novel methodologic approach that integrates genetic and traditional epidemiology to efficiently identify novel cancer biomarkers.
Impact:
Our results find compelling evidence in favor of a protective role for a circulating metabolite, IVC, in lung cancer etiology. From the treatment of a Mendelian disease, isovaleric acidemia, we know that circulating IVC is modifiable through a restricted protein diet or glycine and L-carnatine supplementation. IVC may represent a modifiable and inversely associated biomarker for lung cancer.
Tobacco exposure causes 8 of 10 lung cancers, and identifying additional risk factors is challenging due to confounding introduced by smoking in traditional observational studies.
Materials and Methods:
We used Mendelian randomization (MR) to screen 207 metabolites for their role in lung cancer predisposition using independent genome-wide association studies (GWAS) of blood metabolite levels (n = 7,824) and lung cancer risk (n = 29,266 cases/56,450 controls). A nested case–control study (656 cases and 1,296 matched controls) was subsequently performed using prediagnostic blood samples to validate MR association with lung cancer incidence data from population-based cohorts (EPIC and NSHDS).
Results:
An MR-based scan of 207 circulating metabolites for lung cancer risk identified that blood isovalerylcarnitine (IVC) was associated with a decreased odds of lung cancer after accounting for multiple testing (log10-OR = 0.43; 95% CI, 0.29–0.63). Molar measurement of IVC in prediagnostic blood found similar results (log10-OR = 0.39; 95% CI, 0.21–0.72). Results were consistent across lung cancer subtypes.
Conclusions:
Independent lines of evidence support an inverse association of elevated circulating IVC with lung cancer risk through a novel methodologic approach that integrates genetic and traditional epidemiology to efficiently identify novel cancer biomarkers.
Impact:
Our results find compelling evidence in favor of a protective role for a circulating metabolite, IVC, in lung cancer etiology. From the treatment of a Mendelian disease, isovaleric acidemia, we know that circulating IVC is modifiable through a restricted protein diet or glycine and L-carnatine supplementation. IVC may represent a modifiable and inversely associated biomarker for lung cancer.
| Original language | English |
|---|---|
| Article number | EPI-21-1033 |
| Pages (from-to) | 1966-1974 |
| Number of pages | 9 |
| Journal | Cancer Epidemiology, Biomarkers and Prevention |
| Volume | 31 |
| Issue number | 10 |
| DOIs | |
| Publication status | Published - 4 Oct 2022 |
Bibliographical note
Funding Information:A. Cerani reports grants and other support from Canadian institutes of health research and grants and other support from Fonds de Recherche Québec, Santé, during the conduct of the study. S. Zhou reports grants from CIHR outside the submitted work. C.H. Borchers reports Chief Scientific Officer at MRM Proteomics Inc, a spin off company of the University of Victoria. Chief Technology Officer at Molecular You. Chief Scientific Officer at MRM Proteomics Russia, a spin off company of the Skolkovo Institute of Science and Technology, Moscow, Russia.
Funding Information:
Mattias Johansson and Karl Smith-Byrne were supported by grants from the US National Cancer Institute under award number U19CA203654 and Cancer Research UK (C18281/A29019). This work was also supported by the Canadian Institutes of Health Research, the Canadian Foundation for Innovation, the Fonds de Recherche SantéQuébec (FRSQ), and the FRQS Clinical Research Scholarship. Metabolite GWAS studies were conducted within TwinsUK, which is funded by the Wellcome Trust, Medical Research Council, European Union, the National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility, and Biomedical Research Centre based at Guy’s and St Thomas’s NHS Foundation Trust in partnership with King’s College London. The INTEGRAL-ILCCO OncoArray data collection was supported by National Institute of Health under award number U19CA203654.
Publisher Copyright:
© 2022 The Authors.
Research Groups and Themes
- ICEP
Keywords
- Isovalerylcarnitine
- Lung Cancer
- Metabolite
- Prospective
- EPIC
Access to Document
- Full-text PDF (final published version)
This is the final published version of the article (version of record). It first appeared online via American Association for Cancer Research at https://doi.org/10.1158/1055-9965.EPI-21-1033 . Please refer to any applicable terms of use of the publisher.
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8074 (C18281/A29019) ICEP2 - Programme Award: Towards improved casual evidence and enhanced prediction of cancer risk and survival
Martin, R. M. (Principal Investigator)
1/10/20 → 30/09/25
Project: Research