背景：吸菸已知是肺癌重要的危險因子，而吸菸會透過各種途徑影響肺部基因的表達，其中DNA甲基化為近年受到矚目之表觀基因途徑。目前已有許多研究針對血液組織進行分析，但有研究指出使用肺部組織更能反映吸菸對肺部組織的影響。同時且尚無研究探討DNA甲基化之中介效果，如何解釋抽菸對於肺部組織基因表現的影響。因此我們透過這個研究來釐清DNA甲基化途徑的貢獻性，釐清甲基化作用在眾多表觀基因途徑之中的重要性。
目標：利用因果中介分析(Causal Mediation Analysis)，探討吸菸對基因表達的總效果，及透過DNA甲基化中介影響基因表達的間接效果占總效果的中介比例。
方法：研究族群來自美國癌症基因圖譜計畫(The Cancer Genome Atlas, TCGA)於1991-2013年間被診斷罹患肺腺癌(n=306)及肺鱗狀細胞癌(n=310)的患者，吸菸為暴露變項，基因表達為結果變項，DNA甲基化是中介變項。使用多變量線性迴歸模型，並再校正年齡、性別、種族、癌症分期、癌症種類、KRAS及EGFR突變等之可能擾因素，找出同時與吸菸包年數和基因表達顯著相關的DNA甲基化位點，之後再從Gene Expression Omnibus的選出兩個獨立的驗證資料庫 (GSE66836及GSE66863)，進行兩階段驗證的方式。經此流程篩選出之基因位點，再透過迴歸分析方法得到總效果及間接效果，並計算DNA甲基化所帶來的中介比例。
結果：重度吸菸族群相較於輕度吸菸的族群，其有較高之吸菸包年數(62.09及21.34)，且該族群男性較多、年紀稍長、較多為白人，且有較多人罹患肺鱗狀細胞癌。再經由一連串的分析以及外部驗證之後，我們篩選出在六個DNA甲基化位點，分別坐落在五個不同之基因(PRDM16、CDK6、NETO2、CD109及FAM171B)。其中在PRDM16找到兩個顯著位點(p-value < 0.05)，該基因是一個轉錄共同調節的因子，他可以調控褐色脂肪組織中的褐色脂肪細胞的發育。在這6個位點所計算的中介效果比例，其中僅CD109這個基因的位點甲基化有顯著中介影響基因表達，該基因是和訊號傳遞有關的GPI-linked細胞表面抗原。
結論：藉由在本研究所發現的六個DNA甲基化位點，說明DNA甲基化在抽菸對於基因表現的途徑中，扮演重要的角色，但由於其他機制對於基因表達的中介效果仍未釐清，因此未來之研究仍值得關注於此議題，更有助於了解DNA甲基化之重要性。

Smoking will affect gene expression of lung tissue by several pathways. Recently, epigenetic focus on DNA methylation, and use blood to reflect the effect of smoking. Some studies indicated that the lung tissue will be a better choice, because it will direct contact with cigarette smoke. There is no study focusing on mediation effect of DNA methylation between smoking and gene expression. To the best of our knowledge, this is the first study using causal mediation analysis to clarify the mediation proportion of DNA methylation. Our study population is from TCGA (The Cancer Genome Atlas), who diagnosis with lung adenocarcinoma (LUAD) and lung squamous cell cancer (LUSC). We applied multiple linear regression to analyze the association of smoking to DNA methylation and DNA methylation to gene expression, adjusted for age, sex, race, cancer type, cancer stage, KRAS mutation and EGFR mutation. Finally, we externally validated the findings in two other datasets from Gene Expression Omnibus GSE66836 and GSE66863, and further calculated the mediation effect. Totally, six validated CpG sites were validated and they located in on five genes (PRDM16, CDK6, NETO2, CD109 and FAM171B). Over theses six CpG sites, DNA methylation plays an important role between smoking and gene expression, but we still need to clarify other mediation effect of another pathway to know the importance of DNA methylation.

目 錄
中文摘要…………………………………………………………………… i
英文摘要……………………………………………………………………… iii
目錄………………………………………………………………………… iv
圖目錄…………………………………………………………………… vi
表目錄…………………………………………………………………… vii
第一章 前言與研究背景……………………………………… 1
第一節 台灣與全球肺癌及吸菸現況………………………………………………… 1
第二節 DNA甲基化與肺癌基因表達…………………………………………………… 3
第三節 吸菸造成DNA甲基化…………………………………………………… 5
第四節 吸菸影響肺癌基因表達…………………………………………………… 8
第五節 研究動機與目的…………………………………………………… 10
第二章 材料與方法…………………………………………………………… 11
第一節 研究族群及資料庫………………………………………………… 11
第二節 資料標準化流程…………………………………………………… 15
第三節 研究流程概要…………………………………………………… 17
第四節 統計分析…………………………………………………… 18
第三章 分析結果…………………………………………………………… 24
第一節 人口學變項分布－TCGA………………………………………………… 24
第二節 人口學變項分布－GEO…………………………………………………… 24
第三節 在訓練組（TRAIN）中基因位點之甲基化對基因表達的影響…… 25
第四節 在訓練組（TRAIN）中吸菸包年數對基因位點之甲基化影響 25
第五節 兩階段驗證－內部有效性及外部驗證 26
第六節 因果中介分析 27
第四章 討論…………………………………………………………… 29
第一節 主要發現………………………………………………… 29
第二節 與先前文獻的相似及相異處…………………………………………………… 29
第三節 生物機制…… 31
第四節 吸菸引起公共衛生議題與中介變項分析的主要發現 33
第五節 研究長處 35
第六節 研究限制及未來發展 36
第五章 結論…………………………………………………………… 38



參考文獻………………………………………………………… 39
附錄………………………………………………………………………………. 48

圖 目 錄
圖一、分析流程圖………………………………………………… ……48
圖二、TCGA資料處理流程圖……………………………………………… ……49
圖三、本研究因果中介分析模型………………………………………………… 50
圖四、α與β之p值分佈直方圖………………………………………………… 51
圖五、使用delta method計算中介效果顯著性之p值直方圖…………… ……..52
圖六、基因表達量單位轉換分析結果之差異………………………… 53

表 目 錄
表一、TCGA人口學變項分布……………………………………………………54
表二、GEO人口學變項分布………………………………………………………56
表三、alpha與beta之p-value分布情形…………………………………………57
表四、通過驗證（Validated）的 CpG 位點……………………………………..58
表五、因果中介變項分析結果……………………… 59
表六、常應用於中介變項分析方法之結果………………………… 60
表七、基因表達量FPKM及TPM單位轉換後之分析結果差異………………...61
表八、吸菸對基因表達的影響………………………… 62

Ahn, S. J., Choi, C., Choi, Y. D., Kim, Y. C., Kim, K. S., Oh, I. J., . . . Chung, W. K. (2014). Microarray analysis of gene expression in lung cancer cell lines treated by fractionated irradiation. Anticancer Res, 34(9), 4939-4948.

American Cancer Society. (2018a). Smoking causes more than 16 types of cancer and accounts for a fifth of all global cancer deaths. Retrieved September 7, 2018 from http://canceratlas.cancer.org/risk-factors/tobacco/

American Cancer Society. (2018b). What Is Non-Small Cell Lung Cancer? Retrieved September 7, 2018 from https://www.cancer.org/cancer/non-small-cell-lung-cancer/about/what-is-non-small-cell-lung-cancer.html

Aran, D., Toperoff, G., Rosenberg, M., & Hellman, A. (2011). Replication timing-related and gene body-specific methylation of active human genes. Hum Mol Genet, 20(4), 670-680. doi:10.1093/hmg/ddq513

Baron, R. M., & Kenny, D. A. (1986). The moderator-mediator variable distinction in social psychological research: conceptual, strategic, and statistical considerations. J Pers Soc Psychol, 51(6), 1173-1182.

Bell, J. T., Pai, A. A., Pickrell, J. K., Gaffney, D. J., Pique-Regi, R., Degner, J. F., . . . Pritchard, J. K. (2011). DNA methylation patterns associate with genetic and gene expression variation in HapMap cell lines. Genome Biol, 12(1), R10. doi:10.1186/gb-2011-12-1-r10

Bjaanaes, M. M., Fleischer, T., Halvorsen, A. R., Daunay, A., Busato, F., Solberg, S., . . . Helland, A. (2016). Genome-wide DNA methylation analyses in lung adenocarcinomas: Association with EGFR, KRAS and TP53 mutation status, gene expression and prognosis. Mol Oncol, 10(2), 330-343. doi:10.1016/j.molonc.2015.10.021

Borczuk, A. C., Kim, H. K., Yegen, H. A., Friedman, R. A., & Powell, C. A. (2005). Lung adenocarcinoma global profiling identifies type II transforming growth factor-beta receptor as a repressor of invasiveness. Am J Respir Crit Care Med, 172(6), 729-737. doi:10.1164/rccm.200504-615OC

Borczuk, A. C., Sole, M., Lu, P., Chen, J., Wilgus, M. L., Friedman, R. A., . . . Powell, C. A. (2011). Progression of human bronchioloalveolar carcinoma to invasive adenocarcinoma is modeled in a transgenic mouse model of K-ras-induced lung cancer by loss of the TGF-beta type II receptor. Cancer Res, 71(21), 6665-6675. doi:10.1158/0008-5472.Can-11-1590

Bosse, Y., Postma, D. S., Sin, D. D., Lamontagne, M., Couture, C., Gaudreault, N., . . . Laviolette, M. (2012). Molecular signature of smoking in human lung tissues. Cancer Res, 72(15), 3753-3763. doi:10.1158/0008-5472.Can-12-1160

Breitling, L. P., Yang, R., Korn, B., Burwinkel, B., & Brenner, H. (2011). Tobacco-smoking-related differential DNA methylation: 27K discovery and replication. Am J
Hum Genet, 88(4), 450-457. doi:10.1016/j.ajhg.2011.03.003

Brock, M. V., Hooker, C. M., Ota-Machida, E., Han, Y., Guo, M., Ames, S., . . . Herman, J. G. (2008). DNA methylation markers and early recurrence in stage I lung cancer. N Engl J Med, 358(11), 1118-1128. doi:10.1056/NEJMoa0706550

Centers for Disease Control and Prevention. (2014). Reports of the Surgeon General The Health Consequences of Smoking-50 Years of Progress: A Report of the Surgeon General. Atlanta (GA): Centers for Disease Control and Prevention (US).

Di, Y. P., Zhao, J., & Harper, R. (2012). Cigarette smoke induces MUC5AC protein expression through the activation of Sp1. J Biol Chem, 287(33), 27948-27958. doi:10.1074/jbc.M111.334375

Du, P., Zhang, X., Huang, C. C., Jafari, N., Kibbe, W. A., Hou, L., & Lin, S. M. (2010). Comparison of Beta-value and M-value methods for quantifying methylation levels by microarray analysis. BMC Bioinformatics, 11, 587. doi:10.1186/1471-2105-11-587

Fagerberg, L., Hallstrom, B. M., Oksvold, P., Kampf, C., Djureinovic, D., Odeberg, J., . . . Uhlen, M. (2014). Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics. Mol Cell Proteomics, 13(2), 397-406. doi:10.1074/mcp.M113.035600

Freeman, J. R., Chu, S., Hsu, T., & Huang, Y. T. (2016). Epigenome-wide association study of smoking and DNA methylation in non-small cell lung neoplasms. Oncotarget, 7(43), 69579-69591. doi:10.18632/oncotarget.11831

GBD 2015 Risk Factors Collaborators. (2016). Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: a systematic analysis for the

Global Burden of Disease Study 2015. Lancet, 388(10053), 1659-1724. doi:10.1016/s0140-6736(16)31679-8

Hagiwara, S., Murakumo, Y., Sato, T., Shigetomi, T., Mitsudo, K., Tohnai, I., . . . Takahashi, M. (2008). Up-regulation of CD109 expression is associated with carcinogenesis of the squamous epithelium of the oral cavity. Cancer Sci, 99(10), 1916-1923. doi:10.1111/j.1349-7006.2008.00949.x

Han, L., Lin, I. G., & Hsieh, C. L. (2001). Protein binding protects sites on stable episomes and in the chromosome from de novo methylation. Mol Cell Biol, 21(10), 3416-3424. doi:10.1128/mcb.21.10.3416-3424.2001

Hashimoto, M., Ichihara, M., Watanabe, T., Kawai, K., Koshikawa, K., Yuasa, N., . . . Takahashi, M. (2004). Expression of CD109 in human cancer. Oncogene, 23(20), 3716-3720. doi:10.1038/sj.onc.1207418

Health Promotion Administration. (2014). 癌症發生統計. Retrieved April 15, 2017 from https://data.gov.tw

Health Promotion Administration. (2017). 103年癌症登記年報.

Heinemann, F. G., Tolkach, Y., Deng, M., Schmidt, D., Perner, S., Kristiansen, G., . . . Ellinger, J. (2018). Serum miR-122-5p and miR-206 expression: non-invasive prognostic biomarkers for renal cell carcinoma. Clin Epigenetics, 10, 11. doi:10.1186/s13148-018-0444-9

Huang, J., Okuka, M., Lu, W., Tsibris, J. C., McLean, M. P., Keefe, D. L., & Liu, L. (2013). Telomere shortening and DNA damage of embryonic stem cells induced by cigarette smoke. Reprod Toxicol, 35, 89-95. doi:10.1016/j.reprotox.2012.07.003
Huang, T., Chen, X., Hong, Q., Deng, Z., Ma, H., Xin, Y., . . . Duan, S. (2015). Meta-analyses of gene methylation and smoking behavior in non-small cell lung cancer patients. Sci Rep, 5, 8897. doi:10.1038/srep08897

Huang, Y.-T. (2018). Joint Significance Tests for Mediation Effects of Socioeconomic Adversity on Adiposity via Epigenetics. Annals of Applied Statistics.

Hunter, D. J. (2005). Gene-environment interactions in human diseases. Nat Rev Genet, 6(4), 287-298. doi:10.1038/nrg1578

Jemal, A., Bray, F., Center, M. M., Ferlay, J., Ward, E., & Forman, D. (2011). Global cancer statistics. CA Cancer J Clin, 61(2), 69-90. doi:10.3322/caac.20107

Jha, P., Ramasundarahettige, C., Landsman, V., Rostron, B., Thun, M., Anderson, R. N., . . . Peto, R. (2013). 21st-century hazards of smoking and benefits of cessation in the United States. N Engl J Med, 368(4), 341-350. doi:10.1056/NEJMsa1211128

Jin, B., Li, Y., & Robertson, K. D. (2011). DNA methylation: superior or subordinate in the epigenetic hierarchy? Genes Cancer, 2(6), 607-617. doi:10.1177/1947601910393957

Jjingo, D., Conley, A. B., Yi, S. V., Lunyak, V. V., & Jordan, I. K. (2012). On the presence and role of human gene-body DNA methylation. Oncotarget, 3(4), 462-474. doi:10.18632/oncotarget.497

Joehanes, R., Just, A. C., Marioni, R. E., Pilling, L. C., Reynolds, L. M., Mandaviya, P. R., . . . London, S. J. (2016). Epigenetic Signatures of Cigarette Smoking. Circ Cardiovasc Genet, 9(5), 436-447. doi:10.1161/circgenetics.116.001506

Kadara, H., Fujimoto, J., Yoo, S. Y., Maki, Y., Gower, A. C., Kabbout, M., . . .
Wistuba, II. (2014). Transcriptomic architecture of the adjacent airway field cancerization in non-small cell lung cancer. J Natl Cancer Inst, 106(3), dju004. doi:10.1093/jnci/dju004

Kadonaga, J. T., Carner, K. R., Masiarz, F. R., & Tjian, R. (1987). Isolation of cDNA encoding transcription factor Sp1 and functional analysis of the DNA binding domain. Cell, 51(6), 1079-1090.

Kwon, M. C., E. G.; Jun Na, M.; Min Cho, H.; Jin Kim, Y.; Uee Lee, J.; Jung S., Hye; Mee K., Yoon; Kyeong, K. B.; Woong Son, J. (2007). Identification of DNA methylation markers for NSCLC and adjacent normal lung tissue using Hpall-Mspl Methylation chip: P3-008. Journal of Thoracic Oncology, 2.

Lander, E. S., Linton, L. M., Birren, B., Nusbaum, C., Zody, M. C., Baldwin, J., . . . Szustakowki, J. (2001). Initial sequencing and analysis of the human genome. Nature, 409(6822), 860-921. doi:10.1038/35057062

Law, J. A., & Jacobsen, S. E. (2010). Establishing, maintaining and modifying DNA methylation patterns in plants and animals. Nat Rev Genet, 11(3), 204-220. doi:10.1038/nrg2719

Lee, E. W., & D'Alonzo, G. E. (1993). Cigarette smoking, nicotine addiction, and its pharmacologic treatment. Arch Intern Med, 153(1), 34-48.

Lee, K. W., & Pausova, Z. (2013). Cigarette smoking and DNA methylation. Front Genet, 4, 132. doi:10.3389/fgene.2013.00132
Lenka, G., Tsai, M. H., Lin, H. C., Hsiao, J. H., Lee, Y. C., Lu, T. P., . . . Chuang, E. Y. (2017). Identification of Methylation-Driven, Differentially Expressed STXBP6 as a Novel Biomarker in Lung Adenocarcinoma. Sci Rep, 7, 42573. doi:10.1038/srep42573

Levin, H. L., & Moran, J. V. (2011). Dynamic interactions between transposable elements and their hosts. Nat Rev Genet, 12(9), 615-627. doi:10.1038/nrg3030

Liu, Q., Liu, L., Zhao, Y., Zhang, J., Wang, D., Chen, J., . . . Liu, Z. (2011). Hypoxia induces genomic DNA demethylation through the activation of HIF-1alpha and transcriptional upregulation of MAT2A in hepatoma cells. Mol Cancer Ther, 10(6), 1113-1123. doi:10.1158/1535-7163.Mct-10-1010

Liu, S., Chen, X., Chen, R., Wang, J., Zhu, G., Jiang, J., . . . Huang, J. (2017). Diagnostic role of Wnt pathway gene promoter methylation in non small cell lung cancer. Oncotarget, 8(22), 36354-36367. doi:10.18632/oncotarget.16754
Lokk, K., Vooder, T., Kolde, R., Valk, K., Vosa, U., Roosipuu, R., . . . Tonisson, N. (2012). Methylation markers of early-stage non-small cell lung cancer. PLoS One, 7(6), e39813. doi:10.1371/journal.pone.0039813
MacKinnon, D. P., Lockwood, C. M., Hoffman, J. M., West, S. G., & Sheets, V. (2002). A comparison of methods to test mediation and other intervening variable effects. Psychol Methods, 7(1), 83-104.
MacKinnon, D. P. (2008). Introduction to Statistical Mediation Analysis: Taylor & Francis Group.
Maunakea, A. K., Nagarajan, R. P., Bilenky, M., Ballinger, T. J., D'Souza, C., Fouse, S. D., . . . Costello, J. F. (2010). Conserved role of intragenic DNA methylation in regulating alternative promoters. Nature, 466(7303), 253-257. doi:10.1038/nature09165
McGowan, P. O., Suderman, M., Sasaki, A., Huang, T. C., Hallett, M., Meaney, M. J., & Szyf, M. (2011). Broad epigenetic signature of maternal care in the brain of adult rats. PLoS One, 6(2), e14739. doi:10.1371/journal.pone.0014739
Mercer, B. A., Wallace, A. M., Brinckerhoff, C. E., & D'Armiento, J. M. (2009). Identification of a cigarette smoke-responsive region in the distal MMP-1 promoter. Am J Respir Cell Mol Biol, 40(1), 4-12. doi:10.1165/rcmb.2007-0310OC
Monick, M. M., Beach, S. R., Plume, J., Sears, R., Gerrard, M., Brody, G. H., & Philibert, R. A. (2012). Coordinated changes in AHRR methylation in lymphoblasts and pulmonary macrophages from smokers. Am J Med Genet B Neuropsychiatr Genet, 159b(2), 141-151. doi:10.1002/ajmg.b.32021
Mortusewicz, O., Schermelleh, L., Walter, J., Cardoso, M. C., & Leonhardt, H. (2005). Recruitment of DNA methyltransferase I to DNA repair sites. Proc Natl Acad Sci U S A, 102(25), 8905-8909. doi:10.1073/pnas.0501034102
National Institutes of Health. (2018). About TCGA. Retrieved from https://cancergenome.nih.gov/abouttcga
Ng, E., Lind, P. M., Lindgren, C., Ingelsson, E., Mahajan, A., Morris, A., & Lind, L. (2015). Genome-wide association study of toxic metals and trace elements reveals novel associations. Hum Mol Genet, 24(16), 4739-4745. doi:10.1093/hmg/ddv190
Olson, K. R. (1984). Carbon monoxide poisoning: mechanisms, presentation, and controversies in management. J Emerg Med, 1(3), 233-243.
Opitz, C. A., Litzenburger, U. M., Sahm, F., Ott, M., Tritschler, I., Trump, S., . . . Platten, M. (2011). An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature, 478(7368), 197-203. doi:10.1038/nature10491
Portela, A., & Esteller, M. (2010). Epigenetic modifications and human disease. Nat Biotechnol, 28(10), 1057-1068. doi:10.1038/nbt.1685
Rauch, T., Wang, Z., Zhang, X., Zhong, X., Wu, X., Lau, S. K., . . . Pfeifer, G. P. (2007). Homeobox gene methylation in lung cancer studied by genome-wide analysis with a microarray-based methylated CpG island recovery assay. Proc Natl Acad Sci U S A, 104(13), 5527-5532. doi:10.1073/pnas.0701059104
Risch, A., & Plass, C. (2008). Lung cancer epigenetics and genetics. Int J Cancer, 123(1), 1-7. doi:10.1002/ijc.23605
Satta, R., Maloku, E., Zhubi, A., Pibiri, F., Hajos, M., Costa, E., & Guidotti, A. (2008). Nicotine decreases DNA methyltransferase 1 expression and glutamic acid decarboxylase 67 promoter methylation in GABAergic interneurons. Proc Natl Acad Sci U S A, 105(42), 16356-16361. doi:10.1073/pnas.0808699105
Selamat, S. A., Chung, B. S., Girard, L., Zhang, W., Zhang, Y., Campan, M., . . . Laird-Offringa, I. A. (2012). Genome-scale analysis of DNA methylation in lung adenocarcinoma and integration with mRNA expression. Genome Res, 22(7), 1197-1211. doi:10.1101/gr.132662.111
Shen, J. X., & Yakel, J. L. (2009). Nicotinic acetylcholine receptor-mediated calcium signaling in the nervous system. Acta Pharmacol Sin, 30(6), 673-680. doi:10.1038/aps.2009.64
Shenker, N. S., Polidoro, S., van Veldhoven, K., Sacerdote, C., Ricceri, F., Birrell, M. A., . . . Flanagan, J. M. (2013). 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, 22(5), 843-851. doi:10.1093/hmg/dds488
Shukla, S., Kavak, E., Gregory, M., Imashimizu, M., Shutinoski, B., Kashlev, M., . . . Oberdoerffer, S. (2011). CTCF-promoted RNA polymerase II pausing links DNA methylation to splicing. Nature, 479(7371), 74-79. doi:10.1038/nature10442
Smith, C. J., & Hansch, C. (2000). The relative toxicity of compounds in mainstream cigarette smoke condensate. Food Chem Toxicol, 38(7), 637-646.
Suter, M., Abramovici, A., Showalter, L., Hu, M., Shope, C. D., Varner, M., & Aagaard-Tillery, K. (2010). In utero tobacco exposure epigenetically modifies placental CYP1A1 expression. Metabolism, 59(10), 1481-1490. doi:10.1016/j.metabol.2010.01.013
Suter, M. A., & Aagaard, K. (2012). What changes in DNA methylation take place in individuals exposed to maternal smoking in utero? Epigenomics, 4(2), 115-118. doi:10.2217/epi.12.7
Taiwan Cancer Registry. (2014). 台灣10大癌症98-102年新發個案存活率（追蹤至103年）. Retrieved April 15, 2017 from http://tcr.cph.ntu.edu.tw/main.php?Page=A5B3
Tan, S. X., Hu, R. C., Xia, Q., Tan, Y. L., Liu, J. J., Gan, G. X., & Wang, L. L. (2018). The methylation profiles of PRDM promoters in non-small cell lung cancer. Onco Targets Ther, 11, 2991-3002. doi:10.2147/ott.S156775
Tan, W. W. (2018). Non-Small Cell Lung Cancer. Retrieved September 7, 2018 from https://emedicine.medscape.com/article/279960-overview
Tessema, M., Yingling, C. M., Liu, Y., Tellez, C. S., Van Neste, L., Baylin, S. S., & Belinsky, S. A. (2014). Genome-wide unmasking of epigenetically silenced genes in lung adenocarcinoma from smokers and never smokers. Carcinogenesis, 35(6), 1248-1257. doi:10.1093/carcin/bgt494
Tsukahara, S., Kobayashi, A., Kawabe, A., Mathieu, O., Miura, A., & Kakutani, T. (2009). Bursts of retrotransposition reproduced in Arabidopsis. Nature, 461(7262), 423-426. doi:10.1038/nature08351
van Veldhoven, K., Polidoro, S., Baglietto, L., Severi, G., Sacerdote, C., Panico, S., . . . Vineis, P. (2015). Epigenome-wide association study reveals decreased average methylation levels years before breast cancer diagnosis. Clin Epigenetics, 7, 67. doi:10.1186/s13148-015-0104-2
Wagner, J. R., Busche, S., Ge, B., Kwan, T., Pastinen, T., & Blanchette, M. (2014). The relationship between DNA methylation, genetic and expression inter-individual variation in untransformed human fibroblasts. Genome Biol, 15(2), R37. doi:10.1186/gb-2014-15-2-r37
WHO. (2017). WHO report on the global tobacco epidemic.
World Health Organization. (2013). Tabacco Control. Retrieved February 23, 2017 from http://www.who.int/gho/tobacco/en/
World Health Organization. (2018). Cancer. Retrieved September 7, 2018 from http://www.who.int/en/news-room/fact-sheets/detail/cancer
Yang, I. V., & Schwartz, D. A. (2011). Epigenetic control of gene expression in the lung. Am J Respir Crit Care Med, 183(10), 1295-1301. doi:10.1164/rccm.201010-1579PP
Yue, H., He, J. W., Ke, Y. H., Zhang, H., Wang, C., Hu, W. W., . . . Zhang, Z. L. (2013). Association of single nucleotide polymorphism Rs2236518 in PRDM16 gene with BMI in Chinese males. Acta Pharmacol Sin, 34(5), 710-716. doi:10.1038/aps.2012.201