title: Lung cancer incidence decreases with elevation: evidence for oxygen as an inhaled carcinogen.
abstract: The level of atmospheric oxygen, a driver of free radical damage and tumorigenesis, decreases sharply with rising elevation. To understand whether ambient oxygen plays a role in human carcinogenesis, we characterized age-adjusted cancer incidence (compiled by the National Cancer Institute from 2005 to 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 regression models that captured known risks. Models demonstrated that elevation is strongly, negatively associated with lung cancer incidence (p < 10(-16)), but not with the incidence of non-respiratory cancers. For every 1,000 m 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 ecological fallacy or of confounding arising from evaluated factors 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.
authors: Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors: Kamen P
authors: KP
authors: Simeonov
authors: Biological & Medical Informatics, University of California, San Francisco, CA, USA.
authors: Daniel S
authors: DS
authors: Himmelstein
keywords: Altitude; Cancer incidence; Elevation; Lung cancer; Oxygen
references: J Stat Softw. 2010;33(1):1-22
references: 20808728
references: Am J Clin Nutr. 2008 Aug;88(2):570S-577S
references: 18689404
references: Lancet. 2005 Nov 19;366(9499):1784-93
references: 16298215
references: Radiat Res. 1987 Nov;112(2):381-90
references: 3685264
references: CA Cancer J Clin. 2000 Jan-Feb;50(1):7-33
references: 10735013
references: Health Phys. 2003 Oct;85(4):397-403
references: 13678279
references: Aging Dis. 2013 Dec 05;5(4):274-80
references: 25110611
references: Nat Commun. 2010 Apr 12;1:5
references: 20975668
references: Lancet. 1992 May 23;339(8804):1268-78
references: 1349675
references: J Epidemiol Community Health. 2000 May;54(5):326-7
references: 10814650
references: CA Cancer J Clin. 2014 Jan-Feb;64(1):9-29
references: 24399786
references: Clin Biochem. 1999 Nov;32(8):595-603
references: 10638941
references: J Pediatr. 2005 Jul;147(1):27-31
references: 16027689
references: Ann N Y Acad Sci. 2003 Dec;1010:405-16
references: 15033761
references: Nat Cell Biol. 2003 Aug;5(8):741-7
references: 12855956
references: Med Hypotheses. 2010 Oct;75(4):378-82
references: 20403668
references: Ann Epidemiol. 2005 Nov;15(10):796-803
references: 15922628
references: WMJ. 2009 Aug;108(5):236-9, 255
references: 19743753
references: J Clin Oncol. 2007 Feb 10;25(5):561-70
references: 17290066
references: Nature. 1977 Jun 2;267(5610):423-5
references: 876356
references: PLoS Biol. 2007 May;5(5):e110
references: 17472436
references: Health Phys. 1995 Feb;68(2):157-74
references: 7814250
references: J Pediatr Surg. 2003 Jan;38(1):134-7; discussion 134-7
references: 12592636
references: J Epidemiol Community Health. 2012 Jul;66(7):e17
references: 21406589
references: Acta Paediatr. 2002;91(12):1328-33
references: 12578290
references: Int J Exp Pathol. 2012 Aug;93(4):269-78
references: 22804763
references: Chest. 1985 Dec;88(6):900-5
references: 3905287
references: Am J Epidemiol. 1999 Feb 1;149(3):268-74
references: 9927223
references: BMC Cancer. 2006 Nov 10;6:264
references: 17096841
references: Radiat Res. 1974 Nov;60(2):302-6
references: 10881712
references: PLoS One. 2011 May 12;6(5):e19785
references: 21589870
references: Pediatr Int. 2000 Oct;42(5):492-8
references: 11059537
references: CA Cancer J Clin. 2008 Mar-Apr;58(2):71-96
references: 18287387
references: Am J Public Health. 2005 May;95(5):838-43
references: 15855463
references: Health Phys. 2004 Mar;86(3):316-8; author reply 318
references: 14982234
references: Clin Chest Med. 2002 Mar;23(1):1-25
references: 11901905
references: Carcinogenesis. 1982;3(5):461-5
references: 7094209
references: J Natl Cancer Inst. 1980 Sep;65(3):515-28
references: 6931932
references: J Natl Cancer Inst. 1997 Feb 19;89(4):287-93
references: 9048832
references: Eur J Cancer (1965). 1975 May;11(5):365-71
references: 239848
references: Nature. 1978 Aug 10;274(5671):606-7
references: 353565
references: Annu Rev Pharmacol Toxicol. 2011;51:311-36
references: 20936945
references: Clin Cancer Res. 2009 Sep 15;15(18):5626-45
references: 19755391
references: FASEB J. 2003 Jul;17(10):1195-214
references: 12832285
references: Int J Cancer. 2002 Mar 10;98(2):241-56
references: 11857415
references: BMJ. 2003 Sep 6;327(7414):557-60
references: 12958120