DOI QR코드

DOI QR Code

Relation between RASSF1A Methylation and BRAF Mutation in Thyroid Tumor

갑상선 종양에서 RASSF1A 메틸화와 BRAF 유전자 변이에 관한 연구

  • Oh, Kyoung Ho (Department of Otorhinolaryngology-Head and Neck Surgery, Korea University College of Medicine) ;
  • Jung, Kwang Yoon (Department of Otorhinolaryngology-Head and Neck Surgery, Korea University College of Medicine) ;
  • Baek, Seung Kuk (Department of Otorhinolaryngology-Head and Neck Surgery, Korea University College of Medicine) ;
  • Woo, Jeong Soo (Department of Otorhinolaryngology-Head and Neck Surgery, Korea University College of Medicine) ;
  • Cho, Jae Gu (Department of Otorhinolaryngology-Head and Neck Surgery, Korea University College of Medicine) ;
  • Kwon, Soon Young (Department of Otorhinolaryngology-Head and Neck Surgery, Korea University College of Medicine)
  • 오경호 (고려대학교 의과대학 이비인후-두경부외과학교실) ;
  • 정광윤 (고려대학교 의과대학 이비인후-두경부외과학교실) ;
  • 백승국 (고려대학교 의과대학 이비인후-두경부외과학교실) ;
  • 우정수 (고려대학교 의과대학 이비인후-두경부외과학교실) ;
  • 조재구 (고려대학교 의과대학 이비인후-두경부외과학교실) ;
  • 권순영 (고려대학교 의과대학 이비인후-두경부외과학교실)
  • Received : 2018.10.23
  • Accepted : 2018.11.12
  • Published : 2018.11.30

Abstract

Background and Objectives: Hypermethylation of the tumor suppressor gene RASSF1A and activating mutation of BRAF gene have been recently reported in thyroid cancers. To investigate the role of these two epigenetic and genetic alterations in thyroid tumor progression, methylation of RASSF1A and BRAF mutation were examined in thyroid tumors. Materials and Methods: During 2007 to 2017, 69 papillary carcinomas, 18 nodular hyperplasia, 3 follicular carcinomas, and 13 follicular adenomas were selected. The methylation-specific polymerase chain reaction (MSP) technique was used in detecting RASSF1A methylation and polymerase chain reaction (PCR)-single-stranded conformation polymorphism and sequencing were used for BRAF gene mutation study. Results: The hypermethylation of the RASSF1A gene was found in 84.6%, 100% and 57.9% of follicular adenomas, follicular carcinomas, and papillary carcinomas, respectively. Nodular hyperplasia showed a hypermethylation in 33.3%. The BRAF mutation at V600E was found in 60.7% of papillary carcinoma and 27.0% of nodular hyperplasia, but none of follicular neoplasms. The BRAF mutation was correlated with the lymph node metastasis and MACIS clinical stage. There is an inverse correlation between RASSF1A methylation and BRAF mutation in thyroid lesions. Conclusion: Epigenetic inactivation of RASSF1A through aberrant methylation is considered to be an early step in thyroid tumorigenesis, and the BRAF mutation plays an important role in the carcinogenesis of papillary carcinoma, providing a genetic marker.

Keywords

References

  1. Ministry of Health and Welfare, Korea Cetral Cancer Registry, National Cancer Center. Anual report of cancer statistics in Korea in 2017.
  2. Baylin SB. Mechanisms underlying epigenetically mediated gene silencing in cancer. Semin Cancer Biol 2002;12(5):331-7. https://doi.org/10.1016/S1044-579X(02)00053-6
  3. Kimura ET, Nikiforova MN, Zhu Z, Knauf JA, Nikiforov YE, Fagin JA. 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 2003;63(7):1454-7.
  4. Moretti F, Nanni S, Pontecorvi A. Molecular pathogenesis of thyroid nodules and cancer. Baillieres Best Pract Res Clin Endocrinol Metab 2000;14(4):517-39. https://doi.org/10.1053/beem.2000.0101
  5. Soares P, Trovisco V, Rocha AS, Lima J, Castro P, Preto A, et al. BRAF mutations and RET/PTC rearrangements are alternative events in the etiopathogenesis of PTC. Oncogene 2003;22(29):4578-80. https://doi.org/10.1038/sj.onc.1206706
  6. Namba H, Nakashima M, Hayashi T, Hayashida N, Maeda S, Rogounovitch TI, et al. Clinical implication of hot spot BRAF mutation, V599E, in papillary thyroid cancers. J Clin Endocrinol Metab 2003;88(9):4393-7. https://doi.org/10.1210/jc.2003-030305
  7. Xing M. BRAF mutation in thyroid cancer. Endocr Relat Cancer 2005;12(2):245-62. https://doi.org/10.1677/erc.1.0978
  8. Lerman MI, Minna JD. The 630-kb lung cancer homozygous deletion region on human chromosome 3p21.3: identification and evaluation of the resident candidate tumor suppressor genes. The International Lung Cancer Chromosome 3p21.3 Tumor Suppressor Gene Consortium. Cancer Res 2000;60(21):6116-33.
  9. Agathanggelou A, Honorio S, Macartney DP, Martinez A, Dallol A, Rader J, et al. Methylation associated inactivation of RASSF1A from region 3p21.3 in lung, breast and ovarian tumours. Oncogene 2001;20(12):1509-18. https://doi.org/10.1038/sj.onc.1204175
  10. Burbee DG, Forgacs E, Zochbauer-Muller S, Shivakumar L, Fong K, Gao B, et al. Epigenetic inactivation of RASSF1A in lung and breast cancers and malignant phenotype suppression. J Natl Cancer Inst 2001;93(9):691-9. https://doi.org/10.1093/jnci/93.9.691
  11. Dammann R, Yang G, Pfeifer GP. Hypermethylation of the cpG island of Ras association domain family 1A (RASSF1A), a putative tumor suppressor gene from the 3p21.3 locus, occurs in a large percentage of human breast cancers. Cancer Res 2001;61(7):3105-9.
  12. Xing M, Cohen Y, Mambo E, Tallini G, Udelsman R, Ladenson PW, et al. Early occurrence of RASSF1A hypermethylation and its mutual exclusion with BRAF mutation in thyroid tumorigenesis. Cancer Res 2004;64(5):1664-8. https://doi.org/10.1158/0008-5472.CAN-03-3242
  13. 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.
  14. 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. https://doi.org/10.1078/0344-0338-00436
  15. Harada K, Toyooka S, Maitra A, Maruyama R, Toyooka KO, Timmons CF, et al. Aberrant promoter methylation and silencing of the RASSF1A gene in pediatric tumors and cell lines. Oncogene 2002;21(27):4345-9. https://doi.org/10.1038/sj.onc.1205446
  16. Hawthorn L, Stein L, Varma R, Wiseman S, Loree T, Tan D. TIMP1 and SERPIN-A overexpression and TFF3 and CRABP1 underexpression as biomarkers for papillary thyroid carcinoma. Head Neck 2004;26(12):1069-83. https://doi.org/10.1002/hed.20099
  17. Ito Y, Yoshida H, Tomoda C, Uruno T, Miya A, Kobayashi K, et al. S100A4 expression is an early event of papillary carcinoma of the thyroid. Oncology 2004;67(5-6):397-402. https://doi.org/10.1159/000082924
  18. Kato N, Tsuchiya T, Tamura G, Motoyama T. E-cadherin expression in follicular carcinoma of the thyroid. Pathol Int 2002;52(1):13-8. https://doi.org/10.1046/j.1440-1827.2002.01310.x
  19. 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.
  20. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, et al. Mutations of the BRAF gene in human cancer. Nature 2002;417(6892):949-54. https://doi.org/10.1038/nature00766
  21. Brose MS, Volpe P, Feldman M, Kumar M, Rishi I, Gerrero R, et al. BRAF and RAS mutations in human lung cancer and melanoma. Cancer Res 2002;62(23):6997-7000.
  22. Naoki K, Chen TH, Richards WG, Sugarbaker DJ, Meyerson M. Missense mutations of the BRAF gene in human lung adenocarcinoma. Cancer Res 2002;62(23):7001-3.
  23. Singer G, Oldt R 3rd, Cohen Y, Wang BG, Sidransky D, Kurman RJ, et al. Mutations in BRAF and KRAS characterize the development of low-grade ovarian serous carcinoma. J Natl Cancer Inst 2003;95(6):484-6. https://doi.org/10.1093/jnci/95.6.484
  24. 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. https://doi.org/10.1210/jc.2005-0313

Cited by

  1. The Significance of Transcriptomic Signatures in the Multifocal Papillary Thyroid Carcinoma: Two mRNA Expression Patterns with Distinctive Clinical Behavior from The Cancer Genome Atlas (TCGA) Databas vol.13, pp.1, 2020, https://doi.org/10.11106/ijt.2020.13.1.1