Skip to main content

Advertisement

SpringerLink
Log in

Qualitative and quantitative promoter hypermethylation patterns of the P16, TSHR, RASSF1A and RARβ2 genes in papillary thyroid carcinoma

  • Original Paper
  • Published:
Medical Oncology Aims and scope Submit manuscript

Abstract

The aim of this study was to evaluate the frequency (as qualitative analysis) and level (as quantitative analysis) of promoter hypermethylation of four genes, P16, TSHR, RASSF1A and RARβ2, and to assess their diagnostic or prognostic values in papillary thyroid tumors. Fifty formalin-fixed paraffin-embedded (FFPE) samples consisting of 25 malignant tumors and 25 non-malignant thyroid tumors were analyzed using COBRA method. Promoter hypermethylation of P16, TESH, RASSF1A and RARB2 genes was noted not only in 10, 7, 19 and 13 cases of malignant tumors, but also it was detected in 7, 11, 23 and 8 cases of benign tumors, respectively, limiting its diagnostic usefulness. The quantitative hypermethylation level was significantly higher in malignant tumors compared to benign tumors for P16 (P < 0.004), TSHR (P < 0.006) and RASSF1A (P < 0.001), but the methylation level of RARβ2 (P < 0.31) showed considerable overlap between the two groups. The mean levels of hypermethylation of P16, TSHR and RASSF1A genes were significantly higher in malignant papillary thyroid tumors compared to benign tumors and by choosing the appropriate cutoff for each gene, we could distinguish 9, 9 and 8 PTCs from 25 cases by P16, RASSF1A and TSHR methylation analysis, respectively. According to our results, these three genes, in combination, may be useful as molecular markers. The findings of present study imply that the P16, TSHR and RASSF1A gene promoter hypermethylation may play important roles in the pathogenesis of PTC and can be a potential biomarker for selecting patients with PTC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Mazzaferri EL. Management of a solitary thyroid nodule. N Engl J Med. 1993;328(8):553–9.

    Article  PubMed  CAS  Google Scholar 

  2. Belfiore A, La Rosa GL. Fine-needle aspiration biopsy of the thyroid. Endocrinol Metab Clin North Am. 2001;30(2):361–400.

    Article  PubMed  CAS  Google Scholar 

  3. McCaffrey TV. Evaluation of the thyroid nodule. Cancer Control. 2000;7(3):223–8.

    PubMed  CAS  Google Scholar 

  4. Mohammadi-asl J, Larijani B, Khorgami Z, Tavangar SM, Haghpanah V, Mehdipour P. Prevalence of BRAFV600E mutation in iranian patients with papillary thyroid carcinoma: a single-center study. J Appl Sci. 2009;9(19):3593–7.

    Article  Google Scholar 

  5. Smith JA, Fan CY, Zou C, Bodenner D, Kokoska MS. Methylation status of genes in papillary thyroid carcinoma. Arch Otolaryngol Head Neck Surg. 2007;133(10):1006–11.

    Article  PubMed  Google Scholar 

  6. Fryknas M, Wickenberg-Bolin U, Goransson H, Gustafsson MG, Foukakis T, Lee JJ, et al. Molecular markers for discrimination of benign and malignant follicular thyroid tumors. Tumor Biol. 2006;27(4):211–20.

    Article  Google Scholar 

  7. Haghpanah V, Shooshtarizadeh P, Heshmat R, Larijani B, Tavangar SM. Immunohistochemical analysis of survivin expression in thyroid follicular adenoma and carcinoma. Appl Immunohistochem Mol Morphol. 2006;14(4):422–5.

    Article  PubMed  Google Scholar 

  8. Herman JG. Epigenetic changes in cancer and preneoplasia. Cold Spring Harb Symp Quant Biol. 2005;70:329–33.

    Article  PubMed  CAS  Google Scholar 

  9. Robertson KD, Jones PA. Tissue-specific alternative splicing in the human INK4a/ARF cell cycle regulatory locus. Oncogene. 1999;18(26):3810–20.

    Article  PubMed  CAS  Google Scholar 

  10. Lam AK, Lo CY, Leung P, Lang BH, Chan WF, Luk JM. Clinicopathological roles of alterations of tumor suppressor gene p16 in papillary thyroid carcinoma. Ann Surg Oncol. 2007;14(5):1772–9.

    Article  PubMed  Google Scholar 

  11. Boltze C, Zack S, Quednow C, Bettge S, Roessner A, Schneider-Stock R. Hypermethylation of the CDKN2/p16INK4A promotor in thyroid carcinogenesis. Pathol Res Pract. 2003;199(6):399–404.

    Article  PubMed  CAS  Google Scholar 

  12. Hoque MO, Rosenbaum E, Westra WH, Xing M, Ladenson P, Zeiger MA, et al. Quantitative assessment of promoter methylation profiles in thyroid neoplasms. J Clin Endocrinol Metab. 2005;90(7):4011–8.

    Article  PubMed  CAS  Google Scholar 

  13. Schagdarsurengin U, Gimm O, Dralle H, Hoang-Vu C, Dammann R. CpG island methylation of tumor-related promoters occurs preferentially in undifferentiated carcinoma. Thyroid. 2006;16(7):633–42.

    Article  PubMed  CAS  Google Scholar 

  14. Kopp P. The TSH receptor and its role in thyroid disease. Cell Mol Life Sci. 2001;58(9):1301–22.

    Article  PubMed  CAS  Google Scholar 

  15. Xing M, Usadel H, Cohen Y, Tokumaru Y, Guo Z, Westra WB, et al. Methylation of the thyroid-stimulating hormone receptor gene in epithelial thyroid tumors: a marker of malignancy and a cause of gene silencing. Cancer Res. 2003;63(9):2316–21.

    PubMed  CAS  Google Scholar 

  16. Shivakumar L, Minna J, Sakamaki T, Pestell R, White MA. The RASSF1A tumor suppressor blocks cell cycle progression and inhibits cyclin D1 accumulation. Mol Cell Biol. 2002;22(12):4309–18.

    Article  PubMed  CAS  Google Scholar 

  17. Tommasi S, Dammann R, Zhang Z, Wang Y, Liu L, Tsark WM, et al. Tumor susceptibility of Rassf1a knockout mice. Cancer Res. 2005;65(1):92–8.

    PubMed  CAS  Google Scholar 

  18. Schagdarsurengin U, Gimm O, Hoang-Vu C, Dralle H, Pfeifer GP, Dammann R. Frequent epigenetic silencing of the CpG island promoter of RASSF1A in thyroid carcinoma. Cancer Res. 2002;62(13):3698–701.

    PubMed  CAS  Google Scholar 

  19. Nakamura N, Carney JA, Jin L, Kajita S, Pallares J, Zhang H, et al. RASSF1A and NORE1A methylation and BRAFV600E mutations in thyroid tumors. Lab Invest. 2005;85(9):1065–75.

    Article  PubMed  CAS  Google Scholar 

  20. Soprano DR, Qin P, Soprano KJ. Retinoic acid receptors and cancers. Annu Rev Nutr. 2004;24:201–21.

    Article  PubMed  CAS  Google Scholar 

  21. Xiong Z, Laird PW. COBRA: a sensitive and quantitative DNA methylation assay. Nucleic Acids Res. 1997;25(12):2532–4.

    Article  PubMed  CAS  Google Scholar 

  22. Konishi N, Nakamura M, Kishi M, Nishimine M, Ishida E, Shimada K. Heterogeneous methylation and deletion patterns of the INK4a/ARF locus within prostate carcinomas. Am J Pathol. 2002;160(4):1207–14.

    Article  PubMed  CAS  Google Scholar 

  23. Hu S, Ewertz M, Tufano RP, Brait M, Carvalho AL, Liu D, et al. Detection of serum deoxyribonucleic acid methylation markers: a novel diagnostic tool for thyroid cancer. J Clin Endocrinol Metab. 2006;91(1):98–104.

    Article  PubMed  CAS  Google Scholar 

  24. Ishida E, Nakamura M, Shimada K, Higuchi T, Takatsu K, Yane K, et al. DNA hypermethylation status of multiple genes in papillary thyroid carcinomas. Pathobiology. 2007;74(6):344–52.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Authors would like to thank School of Medicine, Tehran University of Medical Sciences for the financial supports.

Author information

Authors and Affiliations

  1. Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

    Javad Mohammadi-asl, Majid Kheirollahi & Parvin Mehdipour

  2. Endocrinology and Metabolism Research Center (EMRC), School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

    Bagher Larijani & Vahid Haghpanah

  3. Department of Surgery, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran

    Zhamak Khorgami

  4. Department of Pathology, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

    Seyed Mohammad Tavangar

Authors
  1. Javad Mohammadi-asl
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bagher Larijani
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zhamak Khorgami
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Seyed Mohammad Tavangar
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Vahid Haghpanah
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Majid Kheirollahi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Parvin Mehdipour
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Parvin Mehdipour.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mohammadi-asl, J., Larijani, B., Khorgami, Z. et al. Qualitative and quantitative promoter hypermethylation patterns of the P16, TSHR, RASSF1A and RARβ2 genes in papillary thyroid carcinoma. Med Oncol 28, 1123–1128 (2011). https://doi.org/10.1007/s12032-010-9587-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12032-010-9587-z

Keywords

Search

Navigation