Lung cancer incidence decreases with elevation: evidence for oxygen as an inhaled carcinogen
- Published
- Accepted
- Subject Areas
- Epidemiology, Oncology, Public Health, Respiratory Medicine, Statistics
- Keywords
- Cancer Incidence, Lung Cancer, Altitude, Elevation, Oxygen
- Copyright
- © 2014 Simeonov et al.
- Licence
- This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, reproduction and adaptation in any medium and for any purpose provided that it is properly attributed. For attribution, the original author(s), title, publication source (PeerJ PrePrints) and either DOI or URL of the article must be cited.
- Cite this article
- 2014. Lung cancer incidence decreases with elevation: evidence for oxygen as an inhaled carcinogen. PeerJ PrePrints 2:e587v2 https://doi.org/10.7287/peerj.preprints.587v2
Abstract
The atmospheric concentration of oxygen, a driver of free radical damage and tumorigenesis, decreases sharply with rising elevation. To understand whether ambient oxygen concentrations play a role in human carcinogenesis, we characterized age-adjusted cancer incidence (compiled by the National Cancer Institute from 2005–2009) across counties of the elevation-varying Western United States and compared trends displayed by respiratory cancer (lung) and non-respiratory cancers (breast, colorectal, and prostate). To adjust for important demographic and cancer-risk factors, 8–12 covariates were considered for each cancer. We produced sensible regression models that captured known risks. Models demonstrated that elevation strongly, negatively associates with lung cancer incidence (p < 10−16), but not with incidence of non-respiratory cancers. For every 1000 meter rise in elevation, lung cancer incidence decreased by 7.23 [99% CI: 5.18–9.29] cases per 100,000 individuals, equivalent to 12.7% of the mean incidence, 56.8. As a predictor of lung cancer incidence, elevation was second only to smoking prevalence in terms of significance and effect size. Furthermore, no evidence of uncontrolled confounding or ecological fallacy was detected: the lung cancer association was robust to varying regression models, county stratification, and population subgrouping; additionally seven environmental correlates of elevation, such as exposure to sunlight and fine particulate matter, could not capture the association. Overall, our findings suggest the presence of an inhaled carcinogen inherently and inversely tied to elevation, offering epidemiological support for oxygen-driven tumorigenesis. Finally, highlighting the need to consider elevation in studies of lung cancer, we demonstrated that previously reported inverse lung cancer associations with radon and UVB became insignificant after accounting for elevation.
Author Comment
Additions: Prior to posting our preprint (10.7287/peerj.preprints.587v1), we revised our manuscript based on comments from three reviewers and two editors at eLife. PeerJ has now received approval from eLife to publish the reviews. We have added the reviews as well as 'response to reviewers' and 'track changes' files. Per request, all references to reviewer or editor identities have been removed.
Corrections: In Figure 2, the results of the best subset regression models of breast and prostate cancer incidence were outdated. We have updated the figure to the correct version, the only noticeable change being that the optimal breast model contains six variables rather than five. Also, in the Limitations & future directions section of the Discussion, the third sentence of the first paragraph, now correctly reads "all seven pervasive environmental factors". Finally, we optimized figure and table placement to improve readability.
Supplemental Information
Dataset S1. County-level dataset
Tab delimited data collected for US counties. Missing values are blank. Source-reported 95% confidence intervals have ‘lower’ and ‘upper’ appended to the corresponding variable name.
eLife Reviews (public)
Comments and suggestions of eLife senior editor, reviewing editor, and three external peer reviewers. All references to reviewer and editor identities have been removed.
Track changes
Compares the manuscript before and after revision based on the comments of the eLife reviewers.