肺癌的表观遗传学研究进展及其临床意义_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

罗汶鑫 ,  李为民

四川大学华西医院呼吸与危重症医学科（四川成都 610041）;

Corresponding author：

李为民, Email: weimin003@163.com

Keywords：

DOI：

10.7507/1671-6205.201709012

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Citation： 罗汶鑫, 李为民. 肺癌的表观遗传学研究进展及其临床意义. Chinese Journal of Respiratory and Critical Care Medicine, 2018, 17(3): 313-318. doi: 10.7507/1671-6205.201709012 Copy

1.	Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin, 2016, 66(1): 7-30.
2.	Chen W, Zheng R, Baade PD, et al. Cancer statistics in China, 2015. CA Cancer J Clin, 2016, 66(2): 115-132.
3.	Esteller. M. Epigenetics in Cancer. N Engl J Med, 2008, 358(11): 1148-1159.
4.	Ansari J, Shackelford RE, El-Osta H. Epigenetics in non-small cell lung cancer: from basics to therapeutics. Transl Lung Cancer Res, 2016, 5(2): 155-171.
5.	赵建国, 熊建萍. 非小细胞肺癌驱动基因研究进展. 中国肺癌杂志, 2015, 18(1): 42-47.
6.	Mehta A, Dobersch S, Romero-Olmedo AJ, et al. Epigenetics in lung cancer diagnosis and therapy. Cancer Metastasis Rev, 2015, 34(2): 229-241.
7.	Sandoval J, Esteller M. Cancer epigenomics: beyond genomics. Curr Opin Genet Dev, 2012, 22(1): 50-55.
8.	Mari-Alexandre J, Diaz-Lagares A, Villalba M, et al. Translating cancer epigenomics into the clinic: focus on lung cancer. Transl Res, 2017, 189: 76-92.
9.	Sheaffer KL, Elliott EN, Kaestner KH. DNA Hypomethylation Contributes to Genomic Instability and Intestinal Cancer Initiation. Cancer Prev Res, 2016, 9(7): 534-546.
10.	Selamat SA, Galler JS, Joshi AD, et al. DNA methylation changes in atypical adenomatous hyperplasia, adenocarcinoma in situ, and lung adenocarcinoma. PLoS One, 2011, 6(6): e21443.
11.	Sandoval J, Mendez-Gonzalez J, Nadal E, et al. A prognostic DNA methylation signature for stage I non-small-cell lung cancer. J Clin Oncol, 2013, 31(32): 4140-4147.
12.	Lin RK, Hsu HS, Chang JW, et al. Alteration of DNA methyltransferases contributes to 5'CpG methylation and poor prognosis in lung cancer. Lung Cancer, 2007, 55(52): 205-213.
13.	Husni RE, Shiba-Ishii A, Iiyama S, et al. DNMT3a expression pattern and its prognostic value in lung adenocarcinoma. Lung Cancer, 2016, 97: 59-65.
14.	Kneip C, Schmidt B, Seegebarth A, et al. SHOX2 DNA methylation is a biomarker for the diagnosis of lung cancer in plasma. J Thorac Oncol, 2011, 6(10): 1632-1638.
15.	Hubers AJ, Brinkman P, Boksem RJ, et al. Combined sputum hypermethylation and eNose analysis for lung cancer diagnosis. J Clin Pathol, 2014, 67(8): 707-711.
16.	Leng S, Do K, Yingling CM, et al. Defining a gene promoter methylation signature in sputum for lung cancer risk assessment. Clin Cancer Res, 2012, 18(12): 3387-3395.
17.	Diaz-Lagares A, Mendez-Gonzalez J, Hervas D, et al. A Novel Epigenetic Signature for Early Diagnosis in Lung Cancer. Clin Cancer Res, 2016, 22(13): 3361-3371.
18.	Hulbert A, Jusue-Torres, Stark A, et al. Early Detection of Lung Cancer Using DNA Promoter hypermethylation in Plasma and Sputum. Clin Cancer Res, 2017, 23(8): 1998-2005.
19.	Huang H, Sabari BR, Garcia BA, et al. SnapShot: histone modifications. Cell, 2014, 159(2): 458-458.
20.	Arnaudo AM, Garcia BA. Proteomic characterization of novel histone post-translational modifications. Epigenetics Chromatin, 2013, 6(1): 24.
21.	Dawson MA, Kouzarides T. Cancer epigenetics: from mechanism to therapy. Cell, 2012, 150(1): 12-27.
22.	Van Den Broeck A, Brambilla E, Moro-Sibilot D, et al. Loss of histone H4K20 trimethylation occurs in preneoplasia and influences prognosis of non-small cell lung cancer. Clin Cancer Res, 2008, 14(22): 7237-7245.
23.	Seligson DB, Horvath S, McBrian MA, et al. Global levels of histone modifications predict prognosis in different cancers. Am J Pathol, 2009, 174(5): 1619-1628.
24.	Minamiya Y, Ono T, Saito H, et al. Expression of histone deacetylase 1 correlates with a poor prognosis in patients with adenocarcinoma of the lung. Lung Cancer, 2011, 74(2): 300-304.
25.	Roundtree IA, Evans ME, Pan T, et al. Dynamic RNA Modifications in Gene Expression Regulation. Cell, 2017, 169(7): 1187-1200.
26.	Zhao BS, Roundtree IA, He C. Post-transcriptional gene regulation by mRNA modifications. Nat Rev Mol Cell Biol, 2017, 18(1): 31-42.
27.	Deng X, Su R, Feng X, et al. Role of N6-methyladenosine modification in cancer. Curr Opin Genet Dev, 2017, 48: 1-7.
28.	Wang X, Lu Z, Gomez A, et al. N6-methyladenosine-dependent regulation of messenger RNA stability. Nature, 2014, 505(7481): 117-120.
29.	Lin S, Choe J, Du P, et al. The m(6)A Methyltransferase METTL3 Promotes Translation in Human Cancer Cells. Mol Cell, 2016, 62(3): 335-345.
30.	魏文平, 王芳, 张丽华, 等. 甲基转移酶 3 在非小细胞肺癌组织中的表达及其临床意义. 中国临床研究, 2017, 30(6): 748-751.
31.	Langevin SM, Kratzke RA, Kelsey KT. Epigenetics of lung cancer. Transl Res, 2015, 165(1): 74-90.
32.	Lan H, Lu H, Wang X, et al. MicroRNAs as potential biomarkers in cancer: opportunities and challenges. Biomed Res Int, 2015, 2015: 125094.
33.	Baer C, Claus R, Plass C. Genome-wide epigenetic regulation of miRNAs in cancer. Cancer Res, 2013, 73(2): 473-477.
34.	He XY, Chen JX, Zhang Z, et al. The let-7a microRNA protects from growth of lung carcinoma by suppression of k-Ras and c-Myc in nude mice. J Cancer Res Clin Oncol, 2010, 136(7): 1023-1028.
35.	Xia XM, Jin WY, Shi RZ, et al. Clinical significance and the correlation of expression between Let-7 and K-ras in non-small cell lung cancer. Oncol Lett, 2010, 1(6): 1045-1047.
36.	Jiang Z, Yin J, Fu W, et al. MiRNA 17 family regulates cisplatin-resistant and metastasis by targeting TGFbetaR2 in NSCLC. PLoS One, 2014, 9(4): e94639.
37.	Heegaard NH, Schetter AJ, Welsh JA, et al. Circulating micro-RNA expression profiles in early stage nonsmall cell lung cancer. Int J Cancer, 2012, 130(6): 1378-1386.
38.	Yu L, Todd NW, Xing L, et al. Early detection of lung adenocarcinoma in sputum by a panel of microRNA markers. Int J Cancer, 2010, 127(12): 2870-2878.
39.	Cui EH, Li HJ, Hua F, et al. Serum microRNA 125b as a diagnostic or prognostic biomarker for advanced NSCLC patients receiving cisplatin-based chemotherapy. Acta Pharmacol Sin, 2013, 34(2): 309-313.
40.	Zhao Q, Cao J, Wu YC, et al. Circulating miRNAs is a potential marker for gefitinib sensitivity and correlation with EGFR mutational status in human lung cancers. Am J Cancer Res, 2015, 5(5): 1692-1705.
41.	Castillo J, Stueve T, Marconett C. Intersecting transcriptomic profiling technologies and long non-coding RNA function in lung adenocarcinoma: discovery, mechanisms, and therapeutic applications. Oncotarget, 2017, 8: 81538-81557.
42.	Zhang R, Xia Y, Wang Z, et al. Serum long non coding RNA MALAT-1 protected by exosomes is up-regulated and promotes cell proliferation and migration in non-small cell lung cancer. Biochem Biophys Res Commun, 2017, 490(2): 406-414.
43.	Issa JP. DNA methylation as a therapeutic target in cancer. Clin Cancer Res, 2007, 13(6): 1634-1637.
44.	Derissen EJ, Beijnen JH, Schellens JH. Concise drug review: azacitidine and decitabine. Oncologist, 2013, 18(5): 619-624.
45.	Treppendahl MB, Kristensen LS, Gronbaek K. Predicting response to epigenetic therapy. J Clin Invest, 2014, 124(1): 47-55.
46.	Liu SV, Fabbri M, Gitlitz BJ, et al. Epigenetic therapy in lung cancer. Front Oncol, 2013, 3: 135.
47.	Chuang JC, Warner SL, Vollmer D, et al. S110, a 5-Aza-2'-deoxycytidine-containing dinucleotide, is an effective DNA methylation inhibitor in vivo and can reduce tumor growth. Mol Cancer Ther, 2010, 9(5): 1443-1450.
48.	Issa JJ, Roboz G, Rizzieri D, et al. Safety and tolerability of guadecitabine (SGI-110) in patients with myelodysplastic syndrome and acute myeloid leukaemia: a multicentre, randomised, dose-escalation phase 1 study. Lancet Oncol, 2015, 16(9): 1099-1110.
49.	Du Z, Song J, Wang Y, et al. DNMT1 stability is regulated by proteins coordinating deubiquitination and acetylation-driven ubiquitination. Sci Signal, 2010, 3(146): ra80.
50.	Moskowitz AJ, Horwitz SM. Targeting histone deacetylases in T-cell lymphoma. Leuk Lymphoma, 2017, 58(6): 1306-1319.
51.	Forde PM, Brahmer JR, Kelly RJ. New strategies in lung cancer: epigenetic therapy for non-small cell lung cancer. Clin Cancer Res, 2014, 20(9): 2244-2248.
52.	Azad N, Zahnow CA, Rudin CM, et al. The future of epigenetic therapy in solid tumours--lessons from the past. Nat Rev Clin Oncol, 2013, 10(5): 256-266.
53.	Ahuja N, Easwaran H, Baylin SB. Harnessing the potential of epigenetic therapy to target solid tumors. J Clin Invest, 2014, 124(1): 56-63.
54.	Stathis A, Hotte SJ, Chen EX, et al. Phase I study of decitabine in combination with vorinostat in patients with advanced solid tumors and non-Hodgkin's lymphomas. Clin Cancer Res, 2011, 17(6): 1582-1590.
55.	Juergens RA, Wrangle J, Vendetti FP, et al. Combination epigenetic therapy has efficacy in patients with refractory advanced non-small cell lung cancer. Cancer Discov, 2011, 1(7): 598-607.
56.	Ramalingam SS, Maitland ML, Frankel P, et al. Carboplatin and Paclitaxel in combination with either vorinostat or placebo for first-line therapy of advanced non-small-cell lung cancer. J Clin Oncol, 2010, 28(1): 56-62.
57.	Han JY, Lee SH, Lee GK, et al. Phase I/II study of gefitinib (Iressa((R))) and vorinostat (IVORI) in previously treated patients with advanced non-small cell lung cancer. Cancer Chemother Pharmacol, 2015, 75(3): 475-483.
58.	Topalian SL, Drake CG, Pardoll DM. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell, 2015, 27(4): 450-461.
59.	Wrangle J, Wang W, Koch A, et al. Alterations of immune response of Non-Small Cell Lung Cancer with Azacytidine. Oncotarget, 2013, 4(11): 2067-2079.
60.	Chiappinelli KB, Zahnow CA, Ahuja N, et al. Combining Epigenetic and Immunotherapy to Combat Cancer. Cancer Res, 2016, 76(7): 1683-1689.
61.	Delmore JE, Issa GC, Lemieux ME, et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell, 2011, 146(6): 904-917.
62.	Lockwood WW, Zejnullahu K, Bradner JE, et al. Sensitivity of human lung adenocarcinoma cell lines to targeted inhibition of BET epigenetic signaling proteins. Proc Natl Acad Sci USA, 2012, 109(47): 19408-19413.
63.	Lu C, Ward PS, Kapoor GS, et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature, 2012, 483(7390): 474-478.
64.	Turcan S, Rohle D, Goenka A, et al. IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature, 2012, 483(7390): 479-483.
65.	Ye D, Ma S, Xiong Y, et al. R-2-hydroxyglutarate as the key effector of IDH mutations promoting oncogenesis. Cancer Cell, 2013, 23(3): 274-276.
66.	Marcucci G, Maharry K, Wu YZ, et al. IDH1 and IDH2 gene mutations identify novel molecular subsets within de novo cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study. J Clin Oncol, 2010, 28(14): 2348-2355.
67.	Gupta R, Flanagan S, Li CC, et al. Expanding the spectrum of IDH1 mutations in gliomas. Mod Pathol, 2013, 26(5): 619-625.
68.	Tan F, Jiang Y, Sun N, et al. Identification of isocitrate dehydrogenase 1 as a potential diagnostic and prognostic biomarker for non-small cell lung cancer by proteomic analysis. Mol Cell Proteomics, 2012, 11(2): M111.008821.
69.	Kim ES. Enasidenib: First Global Approval. Drugs, 2017.
70.	Park S, Lee J, Lee SY. IDH-Inhibiting Small Molecule DTDQ Inhibits Migration and Invasion of A549 Human Non-Small-Cell Lung Cancer Cells via Sequential Inactivation Of ERK and P38 Signaling Pathways. Cell Biochem Biophys, 2017.
71.	Mohammad HP, Smitheman KN, Kamat CD, et al. A DNA Hypomethylation Signature Predicts Antitumor Activity of LSD1 Inhibitors in SCLC. Cancer Cell, 2015, 28(1): 57-69.
72.	Maes T, Mascaro C, Ortega A, et al. KDM1 histone lysine demethylases as targets for treatments of oncological and neurodegenerative disease. Epigenomics, 2015, 7(4): 609-626.
73.	Jones PA, Issa JP, Baylin S. Targeting the cancer epigenome for therapy. Nat Rev Genet, 2016, 17(10): 630-641.
74.	Fillmore CM, Xu C, Desai PT, et al. EZH2 inhibition sensitizes BRG1 and EGFR mutant lung tumours to TopoII inhibitors. Nature, 2015, 520(7546): 239-242.

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin, 2016, 66(1): 7-30.
2. Chen W, Zheng R, Baade PD, et al. Cancer statistics in China, 2015. CA Cancer J Clin, 2016, 66(2): 115-132.
3. Esteller. M. Epigenetics in Cancer. N Engl J Med, 2008, 358(11): 1148-1159.
4. Ansari J, Shackelford RE, El-Osta H. Epigenetics in non-small cell lung cancer: from basics to therapeutics. Transl Lung Cancer Res, 2016, 5(2): 155-171.
5. 赵建国, 熊建萍. 非小细胞肺癌驱动基因研究进展. 中国肺癌杂志, 2015, 18(1): 42-47.
6. Mehta A, Dobersch S, Romero-Olmedo AJ, et al. Epigenetics in lung cancer diagnosis and therapy. Cancer Metastasis Rev, 2015, 34(2): 229-241.
7. Sandoval J, Esteller M. Cancer epigenomics: beyond genomics. Curr Opin Genet Dev, 2012, 22(1): 50-55.
8. Mari-Alexandre J, Diaz-Lagares A, Villalba M, et al. Translating cancer epigenomics into the clinic: focus on lung cancer. Transl Res, 2017, 189: 76-92.
9. Sheaffer KL, Elliott EN, Kaestner KH. DNA Hypomethylation Contributes to Genomic Instability and Intestinal Cancer Initiation. Cancer Prev Res, 2016, 9(7): 534-546.
10. Selamat SA, Galler JS, Joshi AD, et al. DNA methylation changes in atypical adenomatous hyperplasia, adenocarcinoma in situ, and lung adenocarcinoma. PLoS One, 2011, 6(6): e21443.
11. Sandoval J, Mendez-Gonzalez J, Nadal E, et al. A prognostic DNA methylation signature for stage I non-small-cell lung cancer. J Clin Oncol, 2013, 31(32): 4140-4147.
12. Lin RK, Hsu HS, Chang JW, et al. Alteration of DNA methyltransferases contributes to 5'CpG methylation and poor prognosis in lung cancer. Lung Cancer, 2007, 55(52): 205-213.
13. Husni RE, Shiba-Ishii A, Iiyama S, et al. DNMT3a expression pattern and its prognostic value in lung adenocarcinoma. Lung Cancer, 2016, 97: 59-65.
14. Kneip C, Schmidt B, Seegebarth A, et al. SHOX2 DNA methylation is a biomarker for the diagnosis of lung cancer in plasma. J Thorac Oncol, 2011, 6(10): 1632-1638.
15. Hubers AJ, Brinkman P, Boksem RJ, et al. Combined sputum hypermethylation and eNose analysis for lung cancer diagnosis. J Clin Pathol, 2014, 67(8): 707-711.
16. Leng S, Do K, Yingling CM, et al. Defining a gene promoter methylation signature in sputum for lung cancer risk assessment. Clin Cancer Res, 2012, 18(12): 3387-3395.
17. Diaz-Lagares A, Mendez-Gonzalez J, Hervas D, et al. A Novel Epigenetic Signature for Early Diagnosis in Lung Cancer. Clin Cancer Res, 2016, 22(13): 3361-3371.
18. Hulbert A, Jusue-Torres, Stark A, et al. Early Detection of Lung Cancer Using DNA Promoter hypermethylation in Plasma and Sputum. Clin Cancer Res, 2017, 23(8): 1998-2005.
19. Huang H, Sabari BR, Garcia BA, et al. SnapShot: histone modifications. Cell, 2014, 159(2): 458-458.
20. Arnaudo AM, Garcia BA. Proteomic characterization of novel histone post-translational modifications. Epigenetics Chromatin, 2013, 6(1): 24.
21. Dawson MA, Kouzarides T. Cancer epigenetics: from mechanism to therapy. Cell, 2012, 150(1): 12-27.
22. Van Den Broeck A, Brambilla E, Moro-Sibilot D, et al. Loss of histone H4K20 trimethylation occurs in preneoplasia and influences prognosis of non-small cell lung cancer. Clin Cancer Res, 2008, 14(22): 7237-7245.
23. Seligson DB, Horvath S, McBrian MA, et al. Global levels of histone modifications predict prognosis in different cancers. Am J Pathol, 2009, 174(5): 1619-1628.
24. Minamiya Y, Ono T, Saito H, et al. Expression of histone deacetylase 1 correlates with a poor prognosis in patients with adenocarcinoma of the lung. Lung Cancer, 2011, 74(2): 300-304.
25. Roundtree IA, Evans ME, Pan T, et al. Dynamic RNA Modifications in Gene Expression Regulation. Cell, 2017, 169(7): 1187-1200.
26. Zhao BS, Roundtree IA, He C. Post-transcriptional gene regulation by mRNA modifications. Nat Rev Mol Cell Biol, 2017, 18(1): 31-42.
27. Deng X, Su R, Feng X, et al. Role of N6-methyladenosine modification in cancer. Curr Opin Genet Dev, 2017, 48: 1-7.
28. Wang X, Lu Z, Gomez A, et al. N6-methyladenosine-dependent regulation of messenger RNA stability. Nature, 2014, 505(7481): 117-120.
29. Lin S, Choe J, Du P, et al. The m(6)A Methyltransferase METTL3 Promotes Translation in Human Cancer Cells. Mol Cell, 2016, 62(3): 335-345.
30. 魏文平, 王芳, 张丽华, 等. 甲基转移酶 3 在非小细胞肺癌组织中的表达及其临床意义. 中国临床研究, 2017, 30(6): 748-751.
31. Langevin SM, Kratzke RA, Kelsey KT. Epigenetics of lung cancer. Transl Res, 2015, 165(1): 74-90.
32. Lan H, Lu H, Wang X, et al. MicroRNAs as potential biomarkers in cancer: opportunities and challenges. Biomed Res Int, 2015, 2015: 125094.
33. Baer C, Claus R, Plass C. Genome-wide epigenetic regulation of miRNAs in cancer. Cancer Res, 2013, 73(2): 473-477.
34. He XY, Chen JX, Zhang Z, et al. The let-7a microRNA protects from growth of lung carcinoma by suppression of k-Ras and c-Myc in nude mice. J Cancer Res Clin Oncol, 2010, 136(7): 1023-1028.
35. Xia XM, Jin WY, Shi RZ, et al. Clinical significance and the correlation of expression between Let-7 and K-ras in non-small cell lung cancer. Oncol Lett, 2010, 1(6): 1045-1047.
36. Jiang Z, Yin J, Fu W, et al. MiRNA 17 family regulates cisplatin-resistant and metastasis by targeting TGFbetaR2 in NSCLC. PLoS One, 2014, 9(4): e94639.
37. Heegaard NH, Schetter AJ, Welsh JA, et al. Circulating micro-RNA expression profiles in early stage nonsmall cell lung cancer. Int J Cancer, 2012, 130(6): 1378-1386.
38. Yu L, Todd NW, Xing L, et al. Early detection of lung adenocarcinoma in sputum by a panel of microRNA markers. Int J Cancer, 2010, 127(12): 2870-2878.
39. Cui EH, Li HJ, Hua F, et al. Serum microRNA 125b as a diagnostic or prognostic biomarker for advanced NSCLC patients receiving cisplatin-based chemotherapy. Acta Pharmacol Sin, 2013, 34(2): 309-313.
40. Zhao Q, Cao J, Wu YC, et al. Circulating miRNAs is a potential marker for gefitinib sensitivity and correlation with EGFR mutational status in human lung cancers. Am J Cancer Res, 2015, 5(5): 1692-1705.
41. Castillo J, Stueve T, Marconett C. Intersecting transcriptomic profiling technologies and long non-coding RNA function in lung adenocarcinoma: discovery, mechanisms, and therapeutic applications. Oncotarget, 2017, 8: 81538-81557.
42. Zhang R, Xia Y, Wang Z, et al. Serum long non coding RNA MALAT-1 protected by exosomes is up-regulated and promotes cell proliferation and migration in non-small cell lung cancer. Biochem Biophys Res Commun, 2017, 490(2): 406-414.
43. Issa JP. DNA methylation as a therapeutic target in cancer. Clin Cancer Res, 2007, 13(6): 1634-1637.
44. Derissen EJ, Beijnen JH, Schellens JH. Concise drug review: azacitidine and decitabine. Oncologist, 2013, 18(5): 619-624.
45. Treppendahl MB, Kristensen LS, Gronbaek K. Predicting response to epigenetic therapy. J Clin Invest, 2014, 124(1): 47-55.
46. Liu SV, Fabbri M, Gitlitz BJ, et al. Epigenetic therapy in lung cancer. Front Oncol, 2013, 3: 135.
47. Chuang JC, Warner SL, Vollmer D, et al. S110, a 5-Aza-2'-deoxycytidine-containing dinucleotide, is an effective DNA methylation inhibitor in vivo and can reduce tumor growth. Mol Cancer Ther, 2010, 9(5): 1443-1450.
48. Issa JJ, Roboz G, Rizzieri D, et al. Safety and tolerability of guadecitabine (SGI-110) in patients with myelodysplastic syndrome and acute myeloid leukaemia: a multicentre, randomised, dose-escalation phase 1 study. Lancet Oncol, 2015, 16(9): 1099-1110.
49. Du Z, Song J, Wang Y, et al. DNMT1 stability is regulated by proteins coordinating deubiquitination and acetylation-driven ubiquitination. Sci Signal, 2010, 3(146): ra80.
50. Moskowitz AJ, Horwitz SM. Targeting histone deacetylases in T-cell lymphoma. Leuk Lymphoma, 2017, 58(6): 1306-1319.
51. Forde PM, Brahmer JR, Kelly RJ. New strategies in lung cancer: epigenetic therapy for non-small cell lung cancer. Clin Cancer Res, 2014, 20(9): 2244-2248.
52. Azad N, Zahnow CA, Rudin CM, et al. The future of epigenetic therapy in solid tumours--lessons from the past. Nat Rev Clin Oncol, 2013, 10(5): 256-266.
53. Ahuja N, Easwaran H, Baylin SB. Harnessing the potential of epigenetic therapy to target solid tumors. J Clin Invest, 2014, 124(1): 56-63.
54. Stathis A, Hotte SJ, Chen EX, et al. Phase I study of decitabine in combination with vorinostat in patients with advanced solid tumors and non-Hodgkin's lymphomas. Clin Cancer Res, 2011, 17(6): 1582-1590.
55. Juergens RA, Wrangle J, Vendetti FP, et al. Combination epigenetic therapy has efficacy in patients with refractory advanced non-small cell lung cancer. Cancer Discov, 2011, 1(7): 598-607.
56. Ramalingam SS, Maitland ML, Frankel P, et al. Carboplatin and Paclitaxel in combination with either vorinostat or placebo for first-line therapy of advanced non-small-cell lung cancer. J Clin Oncol, 2010, 28(1): 56-62.
57. Han JY, Lee SH, Lee GK, et al. Phase I/II study of gefitinib (Iressa((R))) and vorinostat (IVORI) in previously treated patients with advanced non-small cell lung cancer. Cancer Chemother Pharmacol, 2015, 75(3): 475-483.
58. Topalian SL, Drake CG, Pardoll DM. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell, 2015, 27(4): 450-461.
59. Wrangle J, Wang W, Koch A, et al. Alterations of immune response of Non-Small Cell Lung Cancer with Azacytidine. Oncotarget, 2013, 4(11): 2067-2079.
60. Chiappinelli KB, Zahnow CA, Ahuja N, et al. Combining Epigenetic and Immunotherapy to Combat Cancer. Cancer Res, 2016, 76(7): 1683-1689.
61. Delmore JE, Issa GC, Lemieux ME, et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell, 2011, 146(6): 904-917.
62. Lockwood WW, Zejnullahu K, Bradner JE, et al. Sensitivity of human lung adenocarcinoma cell lines to targeted inhibition of BET epigenetic signaling proteins. Proc Natl Acad Sci USA, 2012, 109(47): 19408-19413.
63. Lu C, Ward PS, Kapoor GS, et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature, 2012, 483(7390): 474-478.
64. Turcan S, Rohle D, Goenka A, et al. IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature, 2012, 483(7390): 479-483.
65. Ye D, Ma S, Xiong Y, et al. R-2-hydroxyglutarate as the key effector of IDH mutations promoting oncogenesis. Cancer Cell, 2013, 23(3): 274-276.
66. Marcucci G, Maharry K, Wu YZ, et al. IDH1 and IDH2 gene mutations identify novel molecular subsets within de novo cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study. J Clin Oncol, 2010, 28(14): 2348-2355.
67. Gupta R, Flanagan S, Li CC, et al. Expanding the spectrum of IDH1 mutations in gliomas. Mod Pathol, 2013, 26(5): 619-625.
68. Tan F, Jiang Y, Sun N, et al. Identification of isocitrate dehydrogenase 1 as a potential diagnostic and prognostic biomarker for non-small cell lung cancer by proteomic analysis. Mol Cell Proteomics, 2012, 11(2): M111.008821.
69. Kim ES. Enasidenib: First Global Approval. Drugs, 2017.
70. Park S, Lee J, Lee SY. IDH-Inhibiting Small Molecule DTDQ Inhibits Migration and Invasion of A549 Human Non-Small-Cell Lung Cancer Cells via Sequential Inactivation Of ERK and P38 Signaling Pathways. Cell Biochem Biophys, 2017.
71. Mohammad HP, Smitheman KN, Kamat CD, et al. A DNA Hypomethylation Signature Predicts Antitumor Activity of LSD1 Inhibitors in SCLC. Cancer Cell, 2015, 28(1): 57-69.
72. Maes T, Mascaro C, Ortega A, et al. KDM1 histone lysine demethylases as targets for treatments of oncological and neurodegenerative disease. Epigenomics, 2015, 7(4): 609-626.
73. Jones PA, Issa JP, Baylin S. Targeting the cancer epigenome for therapy. Nat Rev Genet, 2016, 17(10): 630-641.
74. Fillmore CM, Xu C, Desai PT, et al. EZH2 inhibition sensitizes BRG1 and EGFR mutant lung tumours to TopoII inhibitors. Nature, 2015, 520(7546): 239-242.

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