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DNA methylation changes measured in pre-diagnostic peripheral blood samples are associated with smoking and lung cancer risk.

ABSTRACT: DNA methylation changes are associated with cigarette smoking. We used the Illumina Infinium HumanMethylation450 array to determine whether methylation in DNA from pre-diagnostic, peripheral blood samples is associated with lung cancer risk. We used a case-control study nested within the EPIC-Italy cohort and a study within the MCCS cohort as discovery sets (a total of 552 case-control pairs). We validated the top signals in 429 case-control pairs from another 3 studies. We identified six CpGs for which hypomethylation was associated with lung cancer risk: cg05575921 in the AHRR gene (p-value_pooled ?=?4 × 10^-17 ), cg03636183 in the F2RL3 gene (p-value_pooled ?=?2 × 10 ^{- 13} ), cg21566642 and cg05951221 in 2q37.1 (p-value_pooled ?=?7 × 10^-16 and 1 × 10^-11 respectively), cg06126421 in 6p21.33 (p-value_pooled ?=?2 × 10^-15 ) and cg23387569 in 12q14.1 (p-value_pooled ?=?5 × 10^-7 ). For cg05951221 and cg23387569 the strength of association was virtually identical in never and current smokers. For all these CpGs except for cg23387569, the methylation levels were different across smoking categories in controls (p-values_{heterogeneity} ???1.8 x10 ^{- 7} ), were lowest for current smokers and increased with time since quitting for former smokers. We observed a gain in discrimination between cases and controls measured by the area under the ROC curve of at least 8% (p-values???0.003) in former smokers by adding methylation at the 6 CpGs into risk prediction models including smoking status and number of pack-years. Our findings provide convincing evidence that smoking and possibly other factors lead to DNA methylation changes measurable in peripheral blood that may improve prediction of lung cancer risk.

SUBMITTER: Baglietto L

PROVIDER: S-EPMC5731426 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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DNA methylation changes measured in pre-diagnostic peripheral blood samples are associated with smoking and lung cancer risk.

Baglietto Laura L Ponzi Erica E Haycock Philip P Hodge Allison A Bianca Assumma Manuela M Jung Chol-Hee CH Chung Jessica J Fasanelli Francesca F Guida Florence F Campanella Gianluca G Chadeau-Hyam Marc M Grankvist Kjell K Johansson Mikael M Ala Ugo U Provero Paolo P Wong Ee Ming EM Joo Jihoon J English Dallas R DR Kazmi Nabila N Lund Eiliv E Faltus Christian C Kaaks Rudolf R Risch Angela A Barrdahl Myrto M Sandanger Torkjel M TM Southey Melissa C MC Giles Graham G GG Johansson Mattias M Vineis Paolo P Polidoro Silvia S Relton Caroline L CL Severi Gianluca G

International journal of cancer 20161011 1

DNA methylation changes are associated with cigarette smoking. We used the Illumina Infinium HumanMethylation450 array to determine whether methylation in DNA from pre-diagnostic, peripheral blood samples is associated with lung cancer risk. We used a case-control study nested within the EPIC-Italy cohort and a study within the MCCS cohort as discovery sets (a total of 552 case-control pairs). We validated the top signals in 429 case-control pairs from another 3 studies. We identified six CpGs f ...[more]

PMID: 27632354

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Project description:Background:Smoking has been reported to be associated with peripheral blood DNA methylation, but the causal aspects of the association have rarely been investigated. We aimed to investigate the association and underlying causation between smoking and blood methylation. Methods:The methylation profile of DNA from the peripheral blood, collected as dried blood spots stored on Guthrie cards, was measured for 479 Australian women including 66 monozygotic twin pairs, 66 dizygotic twin pairs, and 215 sisters of twins from 130 twin families using the Infinium HumanMethylation450K BeadChip array. Linear regression was used to estimate associations between methylation at ~?410,000 cytosine-guanine dinucleotides (CpGs) and smoking status. A regression-based methodology for twins, Inference about Causation through Examination of Familial Confounding (ICE FALCON), was used to assess putative causation. Results:At a 5% false discovery rate, 39 CpGs located at 27 loci, including previously reported AHRR, F2RL3, 2q37.1 and 6p21.33, were found to be differentially methylated across never, former and current smokers. For all 39 CpG sites, current smokers had the lowest methylation level. Our study provides the first replication for two previously reported CpG sites, cg06226150 (SLC2A4RG) and cg21733098 (12q24.32). From the ICE FALCON analysis with smoking status as the predictor and methylation score as the outcome, a woman's methylation score was associated with her co-twin's smoking status, and the association attenuated towards the null conditioning on her own smoking status, consistent with smoking status causing changes in methylation. To the contrary, using methylation score as the predictor and smoking status as the outcome, a woman's smoking status was not associated with her co-twin's methylation score, consistent with changes in methylation not causing smoking status. Conclusions:For middle-aged women, peripheral blood DNA methylation at several genomic locations is associated with smoking. Our study suggests that smoking has a causal effect on peripheral blood DNA methylation, but not vice versa.

Dataset Information

DNA methylation changes measured in pre-diagnostic peripheral blood samples are associated with smoking and lung cancer risk.

Publications

DNA methylation changes measured in pre-diagnostic peripheral blood samples are associated with smoking and lung cancer risk.

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