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DNA methylation alterations as therapeutic prospects in thyroid cancer

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Abstract

Background

Thyroid cancer is one of the most common endocrine malignancies. Although the 10-year survival rate of differentiated thyroid cancer (DTC) is about 90% after conventional treatments, a small proportion of patients still suffer from tumor recurrence or drug resistance.

Objective

This review article summarizes recent researches and clinical trials related to target drugs that reduce mortality in thyroid cancer.

Methods

This is a review of the recent literature and clinical trials on the three main aspects including methylation genes in thyroid cancers, the relationship between BRAF mutation and gene methylation, target and dehypermethylation drugs in clinical trials.

Results

We propose new approaches to treating malignant thyroid cancer, based on advances in understanding the relationship between genetic and epigenetic changes in thyroid cancer. Although the effect of traditional treatment for thyroid cancer is relatively good, a small proportion of patients still suffer from tumor recurrence or drug resistance. Molecular targeted drugs and dehypermethylation drugs have more promising outcomes in aggressive thyroid cancer compared with conventional treatments.

Conclusion

Based on what was discussed in this review, we suggest that integration of epigenetic and targeted therapies into conventional treatments will reduce the occurrence of refractory radioiodine differentiated thyroid cancer and improve the outcomes in aggressive thyroid cancer patients.

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References

  1. Siegel R, Naishadham D, Jemal A (2013) Cancer statistics. CA Cancer J Clin 63(1):11–30

    Article  PubMed  Google Scholar 

  2. Sipos J, Mazzaferri EL (2010) Thyroid cancer epidemiology and prognostic variables. Clin Oncol (R Coll Radiol) 22(6):395–404

    Article  CAS  Google Scholar 

  3. Torre LA T, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A (2015) Global cancer statistics, 2012. CA Cancer J Clin 65(2):87–108. https://doi.org/10.3322/caac.21262

    Article  PubMed  Google Scholar 

  4. Hundahl SA, Cady B, Cunningham MP, Mazzaferri E, McKee RF, Rosai J, Shah JP, Fremgen AM, Stewart AK, Hölzer S (2000) Initial results from a prospective cohort study of 5583 cases of thyroid carcinoma treated in the United States during 1996. US and German Thyroid Cancer Study Group. An American College of Surgeons Commission on Cancer Patient Care Evaluation study. Cancer 89(1):202–217

    Article  CAS  PubMed  Google Scholar 

  5. Cho BY, Choi HS, Park YJ (2013) Changes in the clinicopathological characteristics and outcomes of thyroid cancer in Korea over the past four decades. Thyroid 23(7):797–804

    Article  PubMed  PubMed Central  Google Scholar 

  6. Pishkari S, Paryan M, Hashemi M, Baldini E, Mohammadi-Yeganeh S (2018) The role of microRNAs in different types of thyroid carcinoma: a comprehensive analysis to find new miRNA supplementary therapies. J Endocrinol Invest 41(3):269–283

    Article  CAS  PubMed  Google Scholar 

  7. Vu-Phan D, Koenig RJ (2014) Genetics and epigenetics of sporadic thyroid cancer. Mol Cell Endocrinol 386(1–2):55–66

    Article  CAS  PubMed  Google Scholar 

  8. Xing M (2005) BRAF mutation in thyroid cancer. Endocr Relat Cancer 12(2):245–262

    Article  CAS  PubMed  Google Scholar 

  9. Santos JC, Bastos AU, Cerutti JM et al (2013) Correlation of MLH1 and MGMT expression and promoter methylation with genomic instability in patients with thyroid carcinoma. BMC Cancer 13:79

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Guan H, Ji M, Hou P et al (2008) Hypermethylation of the DNA mismatch repair Gene hMLH1 and its association with lymph node metastasis and T1799A BRAF mutation in patients with papillary thyroid cancer. Cancer 113(2):247–255

    Article  CAS  PubMed  Google Scholar 

  11. Zane M, Agostini M, Enzo MV et al (2013) Circulating cell-free DNA, SLC5A8 and SLC26A4 hypermethylation, BRAFV600E: a non-invasive tool panel for early detection of thyroid cancer. Biomed Pharmacother 67(8):723–730

    Article  CAS  PubMed  Google Scholar 

  12. Hu S, Liu D, Tufano RP et al (2006) Association of aberrant methylation of tumor suppressor genes with tumor aggressiveness and BRAF mutation in papillary thyroid cancer. Int J Cancer 119(10):2322–2329

    Article  CAS  PubMed  Google Scholar 

  13. Jones PA, Baylin SB (2002) The fundamental role of epigenetic events in cancer. Nat Rev Genet 3(6):415–428

    Article  CAS  PubMed  Google Scholar 

  14. Davis CD, Uthus EO (2004) DNA methylation, cancer susceptibility, and nutrient interactions. Exp Biol Med (Maywood) 229(10):988–995

    Article  CAS  Google Scholar 

  15. Sun B, Hu L, Luo ZY et al (2016) DNA methylation perspectives in the pathogenesis of autoimmune diseases. Clin Immunol 164:21–27

    Article  CAS  PubMed  Google Scholar 

  16. Xing M (2007) Gene methylation in thyroid tumorigenesis. Endocrinology 148(3):948–953

    Article  CAS  PubMed  Google Scholar 

  17. Tang J, Xiong Y, Zhou HH, Chen XP (2014) DNA methylation and personalized medicine. J Clin Pharm Ther 39(6):621–627

    Article  CAS  PubMed  Google Scholar 

  18. Lv JF, Hu L, Zhuo W (2016) Epigenetic alternations and cancer chemotherapy response. Cancer Chemother Pharmacol 77(4):673–684

    Article  CAS  PubMed  Google Scholar 

  19. Ai S, Shen L, Guo J et al (2012) DNA methylation as a biomarker for neuropsychiatric diseases. Int J Neurosci 122(4):165–176

    Article  CAS  PubMed  Google Scholar 

  20. Liu MZ, McLeod HL, He FZ (2014) Epigenetic perspectives on cancer chemotherapy response. Pharmacogenomics 15(5):699–715

    Article  CAS  PubMed  Google Scholar 

  21. Stephen JK, Chen KM, Merritt J et al (2015) Methylation markers for early detection and differentiation of follicular thyroid cancer subtypes. Cancer Clin Oncol 4(2):1–12

    PubMed  PubMed Central  Google Scholar 

  22. Schagdarsurengin U, Gimm O, Hoang Vu et al (2002) Frequent epigenetic silencing of the CpG island promoter of RASSF1A in thyroid carcinoma. Cancer Res 62(13):3698–3701

    CAS  PubMed  Google Scholar 

  23. Kunstman JW, Korah R, Healy JM (2013) Quantitative assessment of RASSF1A methylation as a putative molecular marker in papillary thyroid carcinoma. Surgery 154(6):1255–1261 (discussion 1261-2)

    Article  PubMed  Google Scholar 

  24. Stephen JK, Chen KM, Merritt J et al (2018) Methylation markers differentiate thyroid cancer from benign nodules. J Endocrinol Invest 41(2):163–170

    Article  CAS  PubMed  Google Scholar 

  25. Anania MC, Sensi M, Radaelli E et al (2011) TIMP3 regulates migration, invasion and in vivo tumorigenicity of thyroid tumor cells. Oncogene 30(27):3011–3023

    Article  CAS  PubMed  Google Scholar 

  26. Adamczewski Z, Makarewicz J, Mikosiński S et al (2006) Application of 13-cis-retinoic acid in patients with 131I scintigraphically negative metastases of differentiated thyroid carcinoma. Endokrynol Pol 57(4):403–406

    PubMed  Google Scholar 

  27. Xing M (2010) Genetic alterations in the phosphatidylinositol-3Kinase/Akt pathway in thyroid cancer. Thyroid 20(7):697–706

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Erol A (2012) Death-associated proliferation kinetic in normal and transformed cells. Cell Cycle 11(8):1512–1516

    Article  CAS  PubMed  Google Scholar 

  29. Hoque MO, Rosenbaum E, Westra WH et al (2005) Quantitative assessment of promoter methylation profiles in thyroid neoplasms. J Clin Endocrinol Metab 90(7):40118

    Article  CAS  Google Scholar 

  30. Mohammadias J, Larijani B, Khorgami Z (2010) Qualitative and quantitative promoter hypermethylation patterns of the P16, TSHR, RASSF1A and RARb2 genes in papillary thyroid carcinoma. Med Oncol 28(4):1123–1128

    Article  CAS  Google Scholar 

  31. Li H, Myeroff L, Smiraglia D et al (2003) SLC5A8, a sodium transporter, is a tumor suppressor gene silenced by methylation in human colon aberrant crypt foci and cancers. Proc Natl Acad Sci USA 100(14):8412–8417

    Article  CAS  PubMed  Google Scholar 

  32. Porra V, Ferraro-Peyret C, Durand C et al (2005) Silencing of the tumor suppressor gene SLC5A8 is associated with BRAF mutations in classical papillary thyroid carcinomas. J Clin Endocrinol Metab 90(5):3028–3035

    Article  CAS  PubMed  Google Scholar 

  33. Xing M, Usadel H, Cohen Y et al (2003) Methylation of the thyroid-stimulating hormone receptor gene in epithelial thyroid tumors: a marker of malignancy and a cause of gene silencing. Cancer Res 63(9):2316–2321

    CAS  PubMed  Google Scholar 

  34. Neumann S, Schuchardt K, Reske A et al (2004) Lack of correlation for sodium iodide symporter mRNA and protein expression and analysis of sodium iodide symporter promoter methylation in benign cold thyroid nodules. Thyroid 14(2):99–111

    Article  CAS  PubMed  Google Scholar 

  35. Galrão AL, Sodré AK, Camargo RY et al (2013) Methylation levels of sodium–iodide symporter (NIS) promoter in benign and malignant thyroid tumors with reduced NIS expression. Endocrine 43:225–229

    Article  CAS  PubMed  Google Scholar 

  36. Galrão AL, Camargo RY, Friguglietti CU et al (2014) Hypermethylation of a new distal sodium/iodide symporter (NIS) enhancer (NDE) is associated with reduced nis expression in thyroid tumors. J Clin Endocrinol Metab 99(6):E944–E952

    Article  CAS  PubMed  Google Scholar 

  37. Mancikova V, Buj R, Castelblanco E et al (2014) DNA methylation profiling of well-differentiated thyroid cancer uncovers markers of recurrence free survival. Int J Cancer 135(3):598–610

    Article  CAS  PubMed  Google Scholar 

  38. Cai LL, Liu GY, Tzeng CM (2016) Genome-wide DNA methylation profiling and its involved molecular pathways from one individual with thyroid malignant/benign tumor and hyperplasia. Medicine (Baltimore) 95(35):e4695

    Article  CAS  Google Scholar 

  39. Kimura ET, Nikiforova MN, Zhu Z et al (2003) High prevalence of BRAF mutations in thyroid cancer: genetic evidence for constitutive activation of the RET/PTC-RAS-BRAF signaling pathway in papillary thyroid carcinoma. Cancer Res 63:1454–1457

    CAS  PubMed  Google Scholar 

  40. Ciampi R, Nikiforov YE (2005) Alterations of the BRAF gene in thyroid tumors. Endocr Pathol 16:163–172

    Article  CAS  PubMed  Google Scholar 

  41. Xing M, Westra WH, Tufano RP et al (2005) BRAF mutation predicts a poorer clinical prognosis for papillary thyroid cancer. J Clin Endocrinol Metab 90(12):6373–6379

    Article  CAS  PubMed  Google Scholar 

  42. Xing M, Alzahrani AS, Carson KA et al (2015) Association between BRAF V600E mutation and recurrence of papillary thyroid cancer. J Clin Oncol 33(1):42–50

    Article  PubMed  Google Scholar 

  43. Galuppini F, Pennelli G, Vianello F et al (2016) BRAF analysis before surgery for papillary thyroid carcinoma: correlation with clinico-pathological features and prognosis in a single-institution prospective experience. Clin Chem Lab Med 54(9):1531–1539

    Article  CAS  PubMed  Google Scholar 

  44. Durante C, Puxeddu E, Ferretti E et al (2007) BRAF mutations in papillary thyroid carcinomas inhibit genes involved in iodine metabolism. J Clin Endocrinol Metab 92(7):2840–2843

    Article  CAS  PubMed  Google Scholar 

  45. Xing M, Cohen Y, Mambo E et al (2004) Early occurrence of RASSF1A hypermethylation and its mutual exclusion with BRAF mutation in thyroid tumorigenesis. Cancer Res 64(5):1664–1668

    Article  CAS  PubMed  Google Scholar 

  46. Hu S, Liu D, Tufano RP et al (2006) Association of aberrant methylation of tumor suppressor genes with tumor aggressiveness and BRAF mutation in papillary thyroid cancer. Int J Cancer 119(10):2322–2329

    Article  CAS  PubMed  Google Scholar 

  47. Hou P, Liu D, Xing M (2011) Genome-wide alterations in gene methylation by the BRAF V600E mutation in papillary thyroid cancer cells. Endocr Relat Cancer 18(6):687–697

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Khan MS, Pandith AA, Masoodi SR et al (2014) Epigenetic silencing of TSHR gene in thyroid cancer patients in relation to their BRAF V600E mutation status. Endocrine 47(2):449–455

    Article  CAS  PubMed  Google Scholar 

  49. Liu D, Hu S, Hou P et al (2007) Suppression of BRAF/MEK/MAP kinase pathway restores expression of iodide-metabolizing genes in thyroid cells expressing the V600E BRAF mutant. Clin Cancer Res 13(4):1341–1349

    Article  CAS  PubMed  Google Scholar 

  50. Choi YW, Kim HJ, Kim YH et al (2014) B-RafV600E inhibits sodium iodide symporter expression via regulation of DNA methyltransferase1. Exp Mol Med 46:e120

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Schlumberger M, Sherman SI (2012) Approach to the patient with advanced differentiated thyroid cancer. Eur J Endocrinol 166(1):5–11

    Article  CAS  PubMed  Google Scholar 

  52. Hoftijzer H, Heemstra KA, Morreau H et al (2009) Beneficial effects of sorafenib on tumor progression, but not on radioiodine uptake, in patients with differentiated thyroid carcinoma. Eur J Endocrinol 161:923–931

    Article  CAS  PubMed  Google Scholar 

  53. Thomas L, Lai SY, Dong W et al (2014) Sorafenib in metastatic thyroid cancer: a systematic review. Oncologist 19(3):251–258

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Ott PA, Hamilton A, Min C et al (2010) A phase II trial of sorafenib in metastatic melanoma with tissue correlates. PLoS One 5(12):e15588

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Sosman JA, Kim KB, Schuchter L et al (2012) Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med 366(8):707–714

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Hauschild A, Grob JJ, Demidov LV et al (2012) Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet 380(9839):358–365

    Article  CAS  Google Scholar 

  57. Flaherty KT, Puzanov I, Kim KB et al (2010) Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med 363(9):809–819

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Kim KB, Cabanillas ME, Lazar AJ et al (2013) Clinical responses to vemurafenib in patients with metastatic papillary thyroid cancer harboring BRAF(V600E) mutation. Thyroid 23(10):1277–1283

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Brose MS, Cabanillas ME, Cohen EE et al (2016) Vemurafenib in patients with BRAFV600E-positive metastatic or unresectable papillary thyroid cancer refractory to radioactive iodine: a non-randomised, multicentre, open-label, phase 2 trial. Lancet Oncol 17(9):1272–1282

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Dadu R, Shah K, Busaidy NL et al (2015) Efficacy and tolerability of vemurafenib in patients with BRAF(V600E)-positive papillary thyroid cancer: M.D. Anderson Cancer Center off label experience. J Clin Endocrinol Metab 100(1):E77–E81

    Article  CAS  PubMed  Google Scholar 

  61. Fujiwara Y, Yamazaki N, Kiyohara Y et al (2018) Safety, tolerability, and pharmacokinetic profile of dabrafenib in Japanese patients with BRAF (V600) mutation-positive solid tumors: a phase 1 study. Invest New Drugs 36(2):259–268

    Article  CAS  PubMed  Google Scholar 

  62. Linnekamp JF, Butter R, Spijker R et al (2017) Clinical and biological effects of demethylating agents on solid tumours—a systematic review. Cancer Treat Rev 54:10–23

    Article  CAS  PubMed  Google Scholar 

  63. Provenzano MJ, Fitzgerald MP, Krager K et al (2007) Increased iodine uptake in thyroid carcinoma after treatment with sodium butyrate and decitabine (5-Aza-dC). Otolaryngol Head Neck Surg 137(5):722–728

    Article  PubMed  Google Scholar 

  64. Choi YW, Kim HJ, Kim YH et al (2014) B-RafV600E inhibits sodium iodide symporter expression via regulation of DNA methyltransferase 1. Exp Mol Med 46:e120

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Gunda V, Cogdill AP, Bernasconi MJ et al (2013) Potential role of 5-aza-2-deoxycytidine induced MAGE-A4 expression in immunotherapy for anaplastic thyroid cancer. Surgery 154(6):1456–1462 (discussion 1462)

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, People’s Republic of China

    K. Zhang, C. Li, J. Liu, X. Tang & Z. Li

  2. Institute of Clinical Pharmacology, Central South University and Hunan Key Laboratory of Pharmacogenetics, Xiangya Road #110, Changsha, 410078, Hunan, People’s Republic of China

    K. Zhang, C. Li, J. Liu, X. Tang & Z. Li

  3. Department of Pharmacy, ZhuZhou Central Hospital, ZhuZhou, 410078, People’s Republic of China

    C. Li

  4. Department of Center for ADR monitoring of Hubei, Wuhan, 430071, People’s Republic of China

    X. Tang

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  1. K. Zhang
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  2. C. Li
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  3. J. Liu
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  4. X. Tang
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  5. Z. Li
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Correspondence to Z. Li.

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This manuscript is a review of the literature and does not contain original research either on animal or on human subjects.

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Zhang, K., Li, C., Liu, J. et al. DNA methylation alterations as therapeutic prospects in thyroid cancer. J Endocrinol Invest 42, 363–370 (2019). https://doi.org/10.1007/s40618-018-0922-0

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  • DOI: https://doi.org/10.1007/s40618-018-0922-0

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