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Hypomethylation of smoking-related genes is associated with future lung cancer in four prospective cohorts.

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.

SUBMITTER: Fasanelli F

PROVIDER: S-EPMC4682166 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Hypomethylation of smoking-related genes is associated with future lung cancer in four prospective cohorts.

Fasanelli Francesca F Baglietto Laura L Ponzi Erica E Guida Florence F Campanella Gianluca G Johansson Mattias M Grankvist Kjell K Johansson Mikael M Assumma Manuela Bianca MB Naccarati Alessio A Chadeau-Hyam Marc M Ala Ugo U Faltus Christian C Kaaks Rudolf R Risch Angela A De Stavola Bianca B Hodge Allison A Giles Graham G GG Southey Melissa C MC Relton Caroline L CL Haycock Philip C PC Lund Eiliv E Polidoro Silvia S Sandanger Torkjel M TM Severi Gianluca G Vineis Paolo P

Nature communications 20151215

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: ...[more]

PMID: 26667048

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Project description:Smoking is one of the most important factors associated with the development of lung cancer. However, the signaling pathways and driver genes in smoking-associated lung adenocarcinoma remain unknown. The present study analyzed 433 samples of smoking-associated lung adenocarcinoma and 75 samples of non-smoking lung adenocarcinoma from the Cancer Genome Atlas database. Gene Ontology (GO) analysis was performed using the Database for Annotation, Visualization and Integrated Discovery and the ggplot2 R/Bioconductor package. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis was performed using the R packages RSQLite and org.Hs.eg.db. Multivariate Cox regression analysis was performed to screen factors associated with patient survival. Kaplan-Meier and receiver operating characteristic curves were used to analyze the potential clinical significance of the identified biomarkers as molecular prognostic markers for the five-year overall survival time. A total of 373 differentially expressed genes (DEGs; |log2-fold change|≥2.0 and P<0.01) were identified, of which 71 were downregulated and 302 were upregulated. These DEGs were associated with 28 significant GO functions and 11 significant KEGG pathways (false discovery rate <0.05). Two hundred thirty-eight proteins were associated with the 373 differentially expressed genes, and a protein-protein interaction network was constructed. Multivariate regression analysis revealed that 7 mRNAs, cytochrome P450 family 17 subfamily A member 1, PKHD1 like 1, retinoid isomerohydrolase RPE65, neurotensin receptor 1, fetuin B, insulin-like growth factor binding protein 1 and glucose-6-phosphatase catalytic subunit, significantly distinguished between non-smoking and smoking-associated adenocarcinomas. Kaplan-Meier analysis demonstrated that patients in the 7 mRNAs-high-risk group had a significantly worse prognosis than those of the low-risk group. The data obtained in the current study suggested that these genes may serve as potential novel prognostic biomarkers of smoking-associated lung adenocarcinoma.

Project description:BACKGROUND:Preterm delivery and sub-optimal fetal growth are associated with each other and affect both mother and infant. Our aim was to determine (i) whether there are detectable differences in DNA methylation between early and late gestation and (ii) whether changes in DNA methylation from entry are associated with spontaneous preterm delivery with and without reduced fetal growth. METHODS:We conducted a case-control study nested within a large prospective cohort. Gene specific methylation was measured by Methyl-Profiler PCR Array in a Human Breast Cancer Signature Panel of 24 genes from maternal peripheral leukocytes genomic DNA at entry and 3rd trimester (sampled at 16 and 30 weeks of gestation, respectively). Clonal bisulfite DNA sequencing was performed to confirm the changes in selected genes (CYP1B1, GADD45A and CXCL12). Multivariable analysis was used for data analysis. RESULTS:There was significantly decrease in DNA methylation in 15 of 24 genes during the 3rd trimester in cases of spontaneous preterm delivery (n=23) as compared to the controls (n=19) (p<0.05-p<0.01 for each gene). Similar results were observed by bisulfite sequencing for 3 genes. The change in DNA methylation between late and early gestation was significantly different in cases (overall decrease in methylation was -4.0 ± 1.5%) compared to the controls (overall increase in methylation was 12.6 ± 2.19%, p<0.0001). A graded pattern of DNA methylation was observed in 15 genes. Cases who delivered preterm with reduced fetal growth had the lowest level of methylation, cases delivering preterm without reduced fetal growth were next and term controls were highest in methylation (p for trend <0.05 to p<0.01 for each gene). Cases of preterm delivery also had significantly lower dietary choline intake. CONCLUSIONS:These data suggest that epigenetic modification is associated with an increased risk of spontaneous preterm delivery, spontaneous preterm delivery with reduced fetal growth in particular.

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Hypomethylation of smoking-related genes is associated with future lung cancer in four prospective cohorts.

Publications

Hypomethylation of smoking-related genes is associated with future lung cancer in four prospective cohorts.

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