Hypomethylation of Smoking-related Genes is Associated with Future Lung Cancer in Four Prospective Cohorts

Overview

Journal Nat Commun

Specialty Biology

Date 2015 Dec 16

PMID 26667048

Citations 129

Authors

Francesca Fasanelli

Laura Baglietto

Erica Ponzi

Florence Guida

Gianluca Campanella

Mattias Johansson

Kjell Grankvist

Mikael Johansson

Manuela Bianca Assumma

Alessio Naccarati

Marc Chadeau-Hyam

Ugo Ala

Christian Faltus

Rudolf Kaaks

Angela Risch

Bianca De Stavola

Allison Hodge

Graham G Giles

Melissa C Southey

Caroline L Relton

Philip C Haycock

Eiliv Lund

Silvia Polidoro

Torkjel M Sandanger

Gianluca Severi

Paolo Vineis

Affiliations

Soon will be listed here.

Abstract

DNA hypomethylation in certain genes is associated with tobacco exposure but it is unknown whether these methylation changes translate into increased lung cancer risk. In an epigenome-wide study of DNA from pre-diagnostic blood samples from 132 case-control pairs in the NOWAC cohort, we observe that the most significant associations with lung cancer risk are for cg05575921 in AHRR (OR for 1 s.d.=0.37, 95% CI: 0.31-0.54, P-value=3.3 × 10(-11)) and cg03636183 in F2RL3 (OR for 1 s.d.=0.40, 95% CI: 0.31-0.56, P-value=3.9 × 10(-10)), previously shown to be strongly hypomethylated in smokers. These associations remain significant after adjustment for smoking and are confirmed in additional 664 case-control pairs tightly matched for smoking from the MCCS, NSHDS and EPIC HD cohorts. The replication and mediation analyses suggest that residual confounding is unlikely to explain the observed associations and that hypomethylation of these CpG sites may mediate the effect of tobacco on lung cancer risk.

Citing Articles

Blood-based biomarkers derived from tumor-informed DNA methylation analysis for lung adenocarcinoma.

Chitta P, Barrow T, Dawangpa A, Christiani D, Poungvarin N, Sae-Lee C Heliyon. 2025; 11(4):e42581.

PMID: 40034277 PMC: 11874551. DOI: 10.1016/j.heliyon.2025.e42581.

Normal bronchial field basal cells show persistent methylome-wide impact of tobacco smoking, including in known cancer genes.

Khulan B, Ye K, Shi M, Waldman S, Marsh A, Siddiqui T Epigenetics. 2025; 20(1):2466382.

PMID: 39980243 PMC: 11849931. DOI: 10.1080/15592294.2025.2466382.

IARC Workshop on the Key Characteristics of Carcinogens: Assessment of End Points for Evaluating Mechanistic Evidence of Carcinogenic Hazards.

DeMarini D, Gwinn W, Watkins E, Reisfeld B, Chiu W, Zeise L Environ Health Perspect. 2025; 133(2):25001.

PMID: 39899356 PMC: 11790013. DOI: 10.1289/EHP15389.

Blood-based DNA methylation markers for lung cancer prediction.

Onwuka J, Guida F, Langdon R, Johansson M, Severi G, Milne R BMJ Oncol. 2025; 3(1):e000334.

PMID: 39886123 PMC: 11234992. DOI: 10.1136/bmjonc-2024-000334.

Vaccines for cancer prevention: exploring opportunities and navigating challenges.

Graciotti M, Kandalaft L Nat Rev Drug Discov. 2024; 24(2):134-150.

PMID: 39622986 DOI: 10.1038/s41573-024-01081-5.

References

Joo J, Wong E, Baglietto L, Jung C, Tsimiklis H, Park D . The use of DNA from archival dried blood spots with the Infinium HumanMethylation450 array. BMC Biotechnol. 2013; 13:23. PMC: 3610215. DOI: 10.1186/1472-6750-13-23. View

Conen D, Everett B, Kurth T, Creager M, Buring J, Ridker P . Smoking, smoking cessation, [corrected] and risk for symptomatic peripheral artery disease in women: a cohort study. Ann Intern Med. 2011; 154(11):719-26. PMC: 3111942. DOI: 10.7326/0003-4819-154-11-201106070-00003. View

Shenker N, Polidoro S, van Veldhoven K, Sacerdote C, Ricceri F, Birrell M . Epigenome-wide association study in the European Prospective Investigation into Cancer and Nutrition (EPIC-Turin) identifies novel genetic loci associated with smoking. Hum Mol Genet. 2012; 22(5):843-51. DOI: 10.1093/hmg/dds488. View

Wan E, Qiu W, Baccarelli A, Carey V, Bacherman H, Rennard S . Cigarette smoking behaviors and time since quitting are associated with differential DNA methylation across the human genome. Hum Mol Genet. 2012; 21(13):3073-82. PMC: 3373248. DOI: 10.1093/hmg/dds135. View

Hallmans G, Agren A, Johansson G, Johansson A, Stegmayr B, Jansson J . Cardiovascular disease and diabetes in the Northern Sweden Health and Disease Study Cohort - evaluation of risk factors and their interactions. Scand J Public Health Suppl. 2003; 61:18-24. DOI: 10.1080/14034950310001432. View

Willemse B, Ten Hacken N, Rutgers B, Lesman-Leegte I, Postma D, Timens W . Effect of 1-year smoking cessation on airway inflammation in COPD and asymptomatic smokers. Eur Respir J. 2005; 26(5):835-45. DOI: 10.1183/09031936.05.00108904. View

Kawachi I, Colditz G, Stampfer M, Willett W, Manson J, Rosner B . Smoking cessation and decreased risk of stroke in women. JAMA. 1993; 269(2):232-6. View

Philibert R, Beach S, Lei M, Brody G . Changes in DNA methylation at the aryl hydrocarbon receptor repressor may be a new biomarker for smoking. Clin Epigenetics. 2013; 5(1):19. PMC: 3819644. DOI: 10.1186/1868-7083-5-19. View

Elliott H, Tillin T, McArdle W, Ho K, Duggirala A, Frayling T . Differences in smoking associated DNA methylation patterns in South Asians and Europeans. Clin Epigenetics. 2014; 6(1):4. PMC: 3915234. DOI: 10.1186/1868-7083-6-4. View

10.

Giles G, English D . The Melbourne Collaborative Cohort Study. IARC Sci Publ. 2002; 156:69-70. View

11.

Vineis P, Schatzkin A, Potter J . Models of carcinogenesis: an overview. Carcinogenesis. 2010; 31(10):1703-9. PMC: 3025741. DOI: 10.1093/carcin/bgq087. View

12.

Ezzati M, Lopez A . Estimates of global mortality attributable to smoking in 2000. Lancet. 2003; 362(9387):847-52. DOI: 10.1016/S0140-6736(03)14338-3. View

13.

Robins J, Greenland S . Identifiability and exchangeability for direct and indirect effects. Epidemiology. 1992; 3(2):143-55. DOI: 10.1097/00001648-199203000-00013. View

14.

Vlaanderen J, Portengen L, Schuz J, Olsson A, Pesch B, Kendzia B . Effect modification of the association of cumulative exposure and cancer risk by intensity of exposure and time since exposure cessation: a flexible method applied to cigarette smoking and lung cancer in the SYNERGY Study. Am J Epidemiol. 2013; 179(3):290-8. PMC: 3895097. DOI: 10.1093/aje/kwt273. View

15.

Mathers C, Loncar D . Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med. 2006; 3(11):e442. PMC: 1664601. DOI: 10.1371/journal.pmed.0030442. View

16.

Vermeulen R, Chadeau-Hyam M . Dynamic aspects of exposure history-do they matter?. Epidemiology. 2012; 23(6):900-1. DOI: 10.1097/EDE.0b013e31826cc1cb. View

17.

Riboli E, Kaaks R . The EPIC Project: rationale and study design. European Prospective Investigation into Cancer and Nutrition. Int J Epidemiol. 1997; 26 Suppl 1:S6-14. DOI: 10.1093/ije/26.suppl_1.s6. View

18.

Houseman E, Accomando W, Koestler D, Christensen B, Marsit C, Nelson H . DNA methylation arrays as surrogate measures of cell mixture distribution. BMC Bioinformatics. 2012; 13:86. PMC: 3532182. DOI: 10.1186/1471-2105-13-86. View

19.

Fortin J, Labbe A, Lemire M, Zanke B, Hudson T, Fertig E . Functional normalization of 450k methylation array data improves replication in large cancer studies. Genome Biol. 2015; 15(12):503. PMC: 4283580. DOI: 10.1186/s13059-014-0503-2. View

20.

Monick M, Beach S, Plume J, Sears R, Gerrard M, Brody G . Coordinated changes in AHRR methylation in lymphoblasts and pulmonary macrophages from smokers. Am J Med Genet B Neuropsychiatr Genet. 2012; 159B(2):141-51. PMC: 3318996. DOI: 10.1002/ajmg.b.32021. View