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Clinical Significance of P16 Gene Methylation in Lung Cancer

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Single-cell Sequencing and Methylation

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1255))

Abstract

Lung cancer is the leading cause of death from cancer in China. The lack of early screening technologies makes most patients to be diagnosed at advanced stages with a poor prognosis which often miss the best treatment opportunities. Thus, identifying biomarkers for minimally invasive detection and prognosis of early stage disease is urgently needed. Genetic and epigenetic alterations that promote tumorigenesis and metastasis exist in multiple cancers. These aberrant alterations usually represent early events in cancer progression suggesting their potential applications as a biomarker for cancer prediction. Studies have shown that DNA methylation is one of the key factors in progression of lung cancer. P16 promoter methylation is one of the most common epigenetic change plays a key role in lung cancer. In this review, we highlight the p16 gene methylation and its clinical significance in lung cancer.

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References

  1. Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F et al (2016) Cancer statistics in China, 2015. CA Cancer J Clin 66:115–132

    Article  PubMed  Google Scholar 

  2. Jiang Y, Liang Y, Li L, Zhou L, Cheng W, Yang X et al (2019) Targeting neddylation inhibits intravascular survival and extravasation of cancer cells to prevent lung-cancer metastasis. Cell Biol Toxicol 35:233–245

    Article  PubMed  Google Scholar 

  3. Toh TB, Lim JJ, Chow EK (2019) Epigenetics of hepatocellular carcinoma. Clin Transl Med 8(1):13

    Article  PubMed  PubMed Central  Google Scholar 

  4. Wu D, Cheng Y, Wang X, CSGT group (2019) Definition of clinical gene tests. Cell Biol Toxicol 35:83–87

    Article  PubMed  Google Scholar 

  5. Gao D, Zhu B, Sun H, Wang X (2017) Mitochondrial DNA methylation and related disease. Adv Exp Med Biol 1038:117–132

    Article  CAS  PubMed  Google Scholar 

  6. Gu J, Wen Y, Zhu S, Hua F, Zhao H, Xu H et al (2013) Association between P(16INK4a) promoter methylation and non-small cell lung cancer: a meta-analysis. PLoS One 8:e60107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Schacker M, Seimetz D (2019) From fiction to science: clinical potentials and regulatory considerations of gene editing. Clin Transl Med 8(1):27

    Article  PubMed  PubMed Central  Google Scholar 

  8. Ghufran MS, Soni P, Kanade SR (2019) Aflatoxin-induced upregulation of protein arginine methyltransferase 5 is mediated by protein kinase C and extracellular signal-regulated kinase. Cell Biol Toxicol 35(1):67–80

    Article  CAS  PubMed  Google Scholar 

  9. Shen K, Cao Z, Zhu R, You L, Zhang T (2019) The dual functional role of MicroRNA-18a (miR-18a) in cancer development. Clin Transl Med 8(1):32

    Article  PubMed  PubMed Central  Google Scholar 

  10. Tahiliani M, Koh KP, Shen Y, Pastor WA, Bandukwala H, Brudno Y et al (2009) Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 324:930–935

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Rhee YY, Lee TH, Song YS, Wen X, Kim H, Jheon S et al (2015) Prognostic significance of promoter CpG island hypermethylation and repetitive DNA hypomethylation in stage I lung adenocarcinoma. Virchows Arch 466:675–683

    Article  CAS  PubMed  Google Scholar 

  12. Gong J, Hendifar A, Tuli R, Chuang J, Cho M, Chung V et al (2018) Combination systemic therapies with immune checkpoint inhibitors in pancreatic cancer: overcoming resistance to single-agent checkpoint blockade. Clin Transl Med 7:32

    Article  PubMed  Google Scholar 

  13. Selamat SA, Galler JS, Joshi AD, Fyfe MN, Campan M, Siegmund KD et al (2011) DNA methylation changes in atypical adenomatous hyperplasia, adenocarcinoma in situ, and lung adenocarcinoma. PLoS One 6:e21443

    Article  CAS  PubMed  Google Scholar 

  14. West J, Beck S, Wang X, Teschendorff AE (2013) An integrative network algorithm identifies age-associated differential methylation interactome hotspots targeting stem-cell differentiation pathways. Sci Rep 3:1630

    Article  PubMed  CAS  Google Scholar 

  15. Liu B, Song J, Luan J, Sun X, Bai J, Wang H et al (2016) Promoter methylation status of tumor suppressor genes and inhibition of expression of DNA methyltransferase 1 in non-small cell lung cancer. Exp Biol Med 241:1531–1539

    Article  CAS  Google Scholar 

  16. Lukas J, Parry D, Aagaard L, Mann DJ, Bartkova J, Strauss M et al (1995) Retinoblastoma-protein-dependent cell-cycle inhibition by the tumour suppressor p16. Nature 375:503–506

    Article  CAS  PubMed  Google Scholar 

  17. Zhao R, Choi BY, Lee MH, Bode AM, Dong Z (2016) Implications of genetic and epigenetic alterations of CDKN2A (p16(INK4a)) in cancer. EBioMedicine 8:30–39

    Article  PubMed  Google Scholar 

  18. Kamb A, Gruis NA, Weaver-Feldhaus J, Liu Q, Harshman K, Tavtigian SV et al (1994) A cell cycle regulator potentially involved in genesis of many tumor types. Science 264:436–440

    Article  CAS  PubMed  Google Scholar 

  19. Witcher M, Emerson BM (2009) Epigenetic silencing of the p16(INK4a) tumor suppressor is associated with loss of CTCF binding and a chromatin boundary. Mol Cell 34:271–284

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Gil J, Peters G (2006) Regulation of the INK4b-ARF-INK4a tumour suppressor locus: all for one or one for all. Nat Rev Mol Cell Biol 7:667–677

    Article  CAS  PubMed  Google Scholar 

  21. Quelle DE, Zindy F, Ashmun RA, Sherr CJ (1995) Alternative reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest. Cell 83:993–1000

    Article  CAS  PubMed  Google Scholar 

  22. Serrano M, Hannon GJ, Beach D (1993) A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature 366:704–707

    Article  CAS  PubMed  Google Scholar 

  23. Kim JC, Choi JS, Roh SA, Cho DH, Kim TW, Kim YS (2010) Promoter methylation of specific genes is associated with the phenotype and progression of colorectal adenocarcinomas. Ann Surg Oncol 17:1767–1776

    Article  PubMed  Google Scholar 

  24. Lin J, Zeng RM, Li RN, Cao WH (2014) Aberrant DNA methylation of the P16, MGMT, and hMLH1 genes in combination with the methylenetetrahydrofolate reductase C677T genetic polymorphism and folate intake in gastric cancer. Genet Mol Res 13:2060–2068

    Article  CAS  PubMed  Google Scholar 

  25. Cui C, Gan Y, Gu L, Wilson J, Liu Z, Zhang B et al (2015) P16-specific DNA methylation by engineered zinc finger methyltransferase inactivates gene transcription and promotes cancer metastasis. Genome Biol 16:252

    Article  PubMed  CAS  Google Scholar 

  26. Fakhry C, Ferris RL (2018) P16 as a prognostic biomarker for nonoropharyngeal squamous cell cancers: avatar or mirage? J Natl Cancer Inst 110:1290–1291

    PubMed  Google Scholar 

  27. Bryant AK, Sojourner EJ, Vitzthum LK, Zakeri K, Shen H, Nguyen C et al (2018) Prognostic role of p16 in nonoropharyngeal head and neck cancer. J Natl Cancer Inst 110:1393–1399

    Article  PubMed  Google Scholar 

  28. Liu Z, Lin H, Gan Y, Cui C, Zhang B, Gu L et al (2019) P16 methylation leads to paclitaxel resistance of advanced non-small cell lung cancer. J Cancer 10:1726–1733

    Article  PubMed  CAS  Google Scholar 

  29. Sekido Y, Fong KM, Minna JD (1998) Progress in understanding the molecular pathogenesis of human lung cancer. Biochim Biophys Acta 1378:F21–F59

    CAS  PubMed  Google Scholar 

  30. Zhang Y, Wang R, Song H, Huang G, Yi J, Zheng Y et al (2011) Methylation of multiple genes as a candidate biomarker in non-small cell lung cancer. Cancer Lett 303:21–28

    Article  CAS  PubMed  Google Scholar 

  31. Jarmalaite S, Kannio A, Anttila S, Lazutka JR, Husgafvel-Pursiainen K (2003) Aberrant p16 promoter methylation in smokers and former smokers with nonsmall cell lung cancer. Int J Cancer 106:913–918

    Article  CAS  PubMed  Google Scholar 

  32. Hauptman N, Glavač D (2013) Long non-coding RNA in cancer. Int J Mol Sci 14:4655–4669

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Portela A, Esteller M (2010) Epigenetic modifications and human disease. Nat Biotechnol 28:1057–1068

    Article  CAS  PubMed  Google Scholar 

  34. Chan V, Tong TM, Chan TP, Tang M, Wan CW, Chan FY et al (2015) Meta-analyses of gene methylation and smoking behavior in non-small cell lung cancer patients. Sci Rep 5:8897

    Article  CAS  Google Scholar 

  35. Liu Y, Lan Q, Siegfried JM, Luketich JD, Keohavong P (2006) Aberrant promoter methylation of p16 and MGMT genes in lung tumors from smoking and never-smoking lung cancer patients. Neoplasia 8:46–51

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Jin M, Kawakami K, Fukui Y, Tsukioka S, Oda M, Watanabe G et al (2009) Different histological types of non-small cell lung cancer have distinct folate and DNA methylation levels. Cancer Sci 100:2325–2330

    Article  CAS  PubMed  Google Scholar 

  37. Raaschou-Nielsen O, Andersen ZJ, Beelen R, Samoli E, Stafoggia M, Weinmayr G et al (2013) Air pollution and lung cancer incidence in 17 European cohorts: prospective analyses from the European Study of Cohorts for Air Pollution Effects (ESCAPE). Lancet Oncol 14:813–822

    Article  PubMed  Google Scholar 

  38. Hystad P, Demers PA, Johnson KC, Carpiano RM, Brauer M (2013) Long-term residential exposure to air pollution and lung cancer risk. Epidemiology 24:762–772

    Article  PubMed  Google Scholar 

  39. Soberanes S, Gonzalez A, Urich D, Chiarella SE, Radigan KA, Osornio-Vargas A et al (2012) Particulate matter air pollution induces hypermethylation of the p16 promoter via a mitochondrial ROS-JNK-DNMT1 pathway. Sci Rep 2:275

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674

    Article  CAS  PubMed  Google Scholar 

  41. Tuo L, Sha S, Huayu Z, Du K (2018) P16 gene promoter methylation as a biomarker for the diagnosis of non-small cell lung cancer: an updated meta-analysis. Thorac Cancer 9:1032–1040

    Article  CAS  PubMed  Google Scholar 

  42. Brock MV, Hooker CM, Ota-Machida E, Han Y, Guo M, Ames S et al (2008) DNA methylation markers and early recurrence in stage I lung cancer. N Engl J Med 358:1118–1128

    Article  CAS  PubMed  Google Scholar 

  43. Shen N, Du J, Zhou H, Chen N, Pan Y, Hoheisel JD et al (2019) A diagnostic panel of DNA methylation biomarkers for lung adenocarcinoma. Front Oncol 9:1281

    Article  PubMed  Google Scholar 

  44. Ooki A, Maleki Z, Tsay JJ, Goparaju C, Brait M, Turaga N et al (2017) A panel of novel detection and prognostic methylated DNA markers in primary non-small cell lung cancer and serum DNA. Clin Cancer Res 23:7141–7152

    Article  CAS  PubMed  Google Scholar 

  45. Zhou Y, Wang X, Qiu X, Shuai Z, Wang C, Zheng F (2018) CDKN2A promoter methylation and hepatocellular carcinoma risk: a meta-analysis. Clin Res Hepatol Gastroenterol 42:529–541

    Article  CAS  PubMed  Google Scholar 

  46. Bai Y, Shen Y, Yuan Q, Lv C, Xing Q (2019) Evaluation of relationship between occurrence of liver cancer and methylation of fragile histidine triad (FHIT) and P16 genes. Med Sci Monit 25:1301–1306

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Rivandi M, Khorrami MS, Fiuji H, Shahidsales S, Hasanzadeh M, Jazayeri MH et al (2018) The 9p21 locus: a potential therapeutic target and prognostic marker in breast cancer. J Cell Physiol 233:5170–5179

    Article  CAS  PubMed  Google Scholar 

  48. Liu D, Peng H, Sun Q, Zhao Z, Yu X, Wang H et al (2017) The indirect efficacy comparison of DNA methylation in sputum for early screening and auxiliary detection of lung cancer: a meta-analysis. Int J Environ Res Public Health 14(7):679

    Article  PubMed Central  CAS  Google Scholar 

  49. Han J, Xu F, Chen N, Qi G, Wei Y, Li H et al (2016) Promoter methylations of RASSF1A and p16 is associated with clinicopathological features in lung cancers. J Cancer Res Ther 12:340–349

    Article  CAS  PubMed  Google Scholar 

  50. Huang X, Wu C, Fu Y, Guo L, Kong X, Cai H (2018) Methylation analysis for multiple gene promoters in non-small cell lung cancers in high indoor air pollution region in China. Bull Cancer 105:746–754

    Article  PubMed  Google Scholar 

  51. Xiao P, Chen J, Zhou F, Lu C, Yang Q, Tao G et al (2014) Methylation of P16 in exhaled breath condensate for diagnosis of non-small cell lung cancer. Lung Cancer 83:56–60

    Article  PubMed  Google Scholar 

  52. El-Sherif WT, Sayed SK, Galal SH, Makhlouf HA, Hassan AT, Yousef HA et al (2016) Diagnostic role of RASSF1A and p16INK4a promoter gene hypermethylation in serum DNA of lung cancer patients: clinicopathological significance. Egypt J Immunol 23:1–16

    PubMed  Google Scholar 

  53. Yang ZP, Qi WB, Sun L, Zhou H, Zhou B, Hu Y (2019) DNA methylation analysis of selected genes for the detection of early-stage lung cancer using circulating cell-free DNA. Adv Clin Exp Med 28:355–360

    Article  PubMed  Google Scholar 

  54. Bradly DP, Gattuso P, Pool M, Basu S, Liptay M, Bonomi P et al (2012) CDKN2A (p16) promoter hypermethylation influences the outcome in young lung cancer patients. Diagn Mol Pathol 21:207–213

    Article  CAS  PubMed  Google Scholar 

  55. Kim DH, Nelson HH, Wiencke JK, Zheng S, Christiani DC, Wain JC et al (2001) p16(INK4a) and histology-specific methylation of CpG islands by exposure to tobacco smoke in non-small cell lung cancer. Cancer Res 61:3419–3424

    CAS  PubMed  Google Scholar 

  56. Wang J, Lee JJ, Wang L, Liu DD, Lu C, Fan YH et al (2004) Value of p16INK4a and RASSF1A promoter hypermethylation in prognosis of patients with resectable non-small cell lung cancer. Clin Cancer Res 10:6119–6125

    Article  CAS  PubMed  Google Scholar 

  57. Gu J, Berman D, Lu C, Wistuba II, Roth JA, Frazier M et al (2006) Aberrant promoter methylation profile and association with survival in patients with non-small cell lung cancer. Clin Cancer Res 12:7329–7338

    Article  CAS  PubMed  Google Scholar 

  58. Lin Q, Geng J, Ma K, Yu J, Sun J, Shen Z et al (2009) RASSF1A, APC, ESR1, ABCB1 and HOXC9, but not p16INK4A, DAPK1, PTEN and MT1G genes were frequently methylated in the stage I non-small cell lung cancer in China. J Cancer Res Clin Oncol 135:1675–1684

    Article  CAS  PubMed  Google Scholar 

  59. Safar AM, Spencer H III, Su X, Coffey M, Cooney CA, Ratnasinghe LD et al (2005) Methylation profiling of archived non-small cell lung cancer: a promising prognostic system. Clin Cancer Res 11:4400–4405

    Article  CAS  PubMed  Google Scholar 

  60. Grote HJ, Schmiemann V, Geddert H, Rohr UP, Kappes R, Gabbert HE et al (2005) Aberrant promoter methylation of p16(INK4a), RARB2 and SEMA3B in bronchial aspirates from patients with suspected lung cancer. Int J Cancer 116:720–725

    Article  CAS  PubMed  Google Scholar 

  61. Kim YT, Lee SH, Sung SW, Kim JH (2005) Can aberrant promoter hypermethylation of CpG islands predict the clinical outcome of non-small cell lung cancer after curative resection? Ann Thorac Surg 79:1180–1188

    Article  PubMed  Google Scholar 

  62. Tanaka R, Wang D, Morishita Y, Inadome Y, Minami Y, Iijima T et al (2003) Loss of function of p16 gene and prognosis of pulmonary adenocarcinoma. Cancer 103(3):608–615

    Google Scholar 

  63. Kim H, Kwon YM, Kim JS, Lee H, Park JH et al (2004) Tumor-specific methylation in bronchial lavage for the early detection of non-small-cell lung cancer. Clin Oncol 22:2363–2370

    Article  CAS  Google Scholar 

  64. Toyooka S, Maruyama R, Toyooka KO, McLerran D, Feng Z, Fukuyama Y et al (2003) Smoke exposure, histologic type and geography-related differences in the methylation profiles of non-small cell lung cancer. Int J Cancer 103:153–160

    Article  CAS  PubMed  Google Scholar 

  65. Yanagawa N, Tamura G, Oizumi H, Takahashi N, Shimazaki Y, Motoyama T (2003) Promoter hypermethylation of tumor suppressor and tumor-related genes in non-small cell lung cancers. Cancer Sci 94(7):589–592

    Article  CAS  PubMed  Google Scholar 

  66. Zochbauer-Muller S, Fong KM, Virmani AK, Geradts J, Gazdar AF, Minna JD (2001) Aberrant promoter methylation of multiple genes in non-small cell lung cancers. Cancer Res 61:249–255

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Center for Clinical Single Cell Biomedicine, Henan Provincial People’s Hospital, Zhengzhou, Henan, China

    Yanjun Li, Tingting Zhang, Hui Zhang, Xiaozhuan Liu & Li Li

  2. Zhengzhou University People’s Hospital, Zhengzhou, Henan, China

    Yanjun Li, Tingting Zhang, Hui Zhang, Xiaozhuan Liu & Li Li

  3. Henan University People’s Hospital, Zhengzhou, Henan, China

    Yanjun Li, Tingting Zhang, Hui Zhang, Xiaozhuan Liu & Li Li

  4. Zhongshan Hospital, Fudan University, Shanghai, Shanghai, China

    Xiangdong Wang & Qihong Huang

  5. Department of Scientific Research and Discipline Construction, Henan Provincial People’s Hospital, Zhengzhou, Henan, China

    Li Li

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  1. Yanjun Li
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  2. Tingting Zhang
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  3. Hui Zhang
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  4. Xiangdong Wang
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  5. Xiaozhuan Liu
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Correspondence to Li Li .

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Editors and Affiliations

  1. Ruijin Hospital, Shanghai Jiao Tong University, Shanghai, Shanghai, China

    Buwei Yu

  2. Department of Anesthesiology and Perioperative Medicine, Center of Clinical Single-Cell Biomedicine, Henan Provincial People’s Hospital, Zhengzhou, University People’s Hospital, Henan University People’s Hospital, Zhengzhou, P.R., China

    Jiaqiang Zhang

  3. 2nd Affiliated Hospital, Fujian Medical University, Quanzhou, Fujian, China

    Yiming Zeng

  4. Centre for Single Cell Biomedicine, Henan Provincial People’s Hospital, Zhengzhou, Henan, China

    Li Li

  5. Zhongshan Hospital, Fudan University, Shanghai, Shanghai, China

    Xiangdong Wang

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Li, Y. et al. (2020). Clinical Significance of P16 Gene Methylation in Lung Cancer. In: Yu, B., Zhang, J., Zeng, Y., Li, L., Wang, X. (eds) Single-cell Sequencing and Methylation. Advances in Experimental Medicine and Biology, vol 1255. Springer, Singapore. https://doi.org/10.1007/978-981-15-4494-1_11

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