Journal List > J Korean Endocr Soc > v.22(3) > 1003361

TOOLS
Jung, Kim, Jung, Oh, Jang, Jung, Min, Lee, Lee, Kim, and Chung: ras Mutation in Korean Papillary Thyroid Carcinomas
Original Article
Journal of Korean Endocrine Society

Journal of Korean Endocrine Society 2007; 22(3): 203-209.

Published online: 20 June 2007

DOI: https://doi.org/10.3803/jkes.2007.22.3.203

ras Mutation in Korean Papillary Thyroid Carcinomas

Jung Hwa Jung, Keun-Sook Kim1, Tae Sik Jung, Young Lyun Oh2, Hye Won Jang, Hye Seung Jung, Yong-Ki Min, Myung-Shik Lee, Moon-Kyu Lee, Kwang-Won Kim, Jae Hoon Chung

Division of Endocrinology and Metabolism, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Korea.

1Samsung Biomedical Research Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Korea.

2Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Korea.

Received 12 February 2007       Accepted 23 March 2007

Copyright © 2007 Korean Endocrine Society

Abstract

Background

RET/PTC rearrangement and mutations of BRAF and ras are well-known oncogenes involved in the pathogenesis of papillary thyroid carcinoma (PTC). The prevalence of RET/PTC rearrangement and BRAF mutations were 0~13% and 66~83% in Korean patients with PTC, respectively. We evaluated the prevalence of ras mutations in surgical specimens of PTC, and we compared them with the patients' clinical features.

Subjects and Methods

We included the surgical specimens of 49 PTCs and a few follicular thyroid carcinomas (FTCs) and follicular adenomas (FAs) as positive controls. Polymerase chain reaction, single strand conformation polymorphism and direct sequence analysis were consecutively performed to detect ras mutations.

Results

No mutations of the ras oncogenes were detected in 49 PTCs. However, heterozygous mutations of the ras oncogenes were found in a FTC and FA as positive controls, respectively.

Conclusion

These findings suggested that ras mutation is not or rarely related to the tumorigenesis of PTCs in Koreans. Therefore, BRAF mutations and RET/PTC rearrangement, rather than ras mutation, might contribute the development of PTC in Koreans.

Keywords: Papillary thyroid carcinoma, Ras oncogene

Figures and Tables

Fig. 1
A. Electrophoresis in 1.0% agarose gel using PCR products of K-, N- and H-ras from papillary thyroid carcinoma. M indicates molecular size marker. B. Representative results of SSCP for N-ras gene using 0.5 × MDE gel. There is no shift of band between 1 (normal control) and 2~4 (from papillary thyroid carcinomas).
jkes-22-203-g001
Fig. 2
Representative direct sequences for exon-2 of N-ras gene using DNA from papillary thyroid carcinoma (A) and follicular carcinoma (B). B shows a mutation in heterozygosity at codon 61 (CAA --- AAA).
jkes-22-203-g002
Table 1
Oligonucleotide primers and PCR conditions to amplify fragments of the ras oncogene
jkes-22-203-i001

PCR; Polymerase chain reaction, "; seconds.

References

1. Barbacid M. ras genes. Ann Rev Biochem. 1987. 56:779–827.
2. Manenti G, Pilotti S, Re FC, Della Porta G, Pierotti MA. Selective activation of ras oncogenes in follicular and undifferentiated thyroid carcinomas. Eur J Cancer. 1994. 30A:987–993.
3. Hara H, Fulton N, Yashiro T, Ito K, DeGroot LJ, Kaplan EL. N-ras mutation: an independent prognostic factor for aggressiveness of papillary thyroid carcinoma. Surgery. 1994. 116:1010–1016.
4. Garcia-Rostan G, Zhao H, Camp RL, Pollan M, Herrero A, Pardo J, Wu R, Carcangiu ML, Costa J, Tallini G. ras mutations are associated with aggressive tumor phenotypes and poor prognosis in thyroid cancer. J Clin Oncol. 2003. 21:3226–3235.
5. 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. 63:1454–1457.
6. Kondo T, Ezzat S, Asa SL. Pathogenetic mechanisms in thyroid follicular-cell neoplasia. Nat Rev Cancer. 2006. 6:292–306.
7. Xing M. BRAF mutation in thyroid cancer. Endocrine-Related Cancer. 2005. 12:245–262.
8. Park KY, Koh JM, Kim YI, Park HJ, Gong G, Hong SJ, Ahn IM. Prevalences of Gs alpha, ras, p53 mutations and ret/PTC rearrangement in differentiated thyroid tumours in a Korean population. Clin Endocrinol (Oxf). 1998. 49:317–323.
9. Chung JH, Hahm JR, Min YK, Lee MS, Lee MK, Kim KW, Nam SJ, Yang JH, Ree HJ. Detection of RET/PTC oncogene rearrangements in Korean papillary thyroid carcinomas. Thyroid. 1999. 9:1237–1243.
10. Kim KH, Kang DW, Kim SH, Seong IO, Kang DY. Mutations of the BRAF gene in papillary thyroid carcinoma in a Korean population. Yonsei Med J. 2004. 45:818–821.
11. Rha SY, Lee JC, Kwon KH, Lee HJ, Kim KS, Jo YS, Ku BJ, Shong M, Kim YK, Ro HK. The relationship between the BRAF mutations in thyroid papillary carcinomas and the prognostic factors. J Korean Soc Endocrinol. 2005. 20:224–229.
12. Kim TY, Kim WB, Rhee YS, Song JY, Kim JM, Gong G, Lee S, Kim SY, Kim SC, Hong SJ, Shong YK. The BRAF mutation is useful for prediction of clinical recurrence in low-risk patients with conventional papillary thyroid carcinoma. Clin Endocrinol (Oxf). 2006. 65:364–368.
13. Park SY, Park YJ, Lee YJ, Lee HS, Choi SH, Choe G, Jang HC, Park SH, Park do J, Cho BY. Analysis of differential BRAF (V600E) mutational status in multifocal papillary thyroid carcinoma: evidence of independent clonal origin in distinct tumor foci. Cancer. 2006. 107:1831–1838.
14. Greene FL, Page DL, Fleming ID, Fritz A, Balch CM, Haller DG, Morrow M. AJCC cancer staging manual. 2002. 6th ed. New York: Springer-Verlag Press;77–79.
15. Patel KN, Singh B. Genetic considerations in thyroid cancer. Cancer Control. 2006. 13:111–118.
16. Puxeddu E, Moretti S, Elisei R, Romei C, Pascucci R, Martinelli M, Marino C, Avenia N, Rossi ED, Fadda G, Cavaliere A, Ribacchi R, Falorni A, Pontecorvi A, Pacini F, Pinchera A, Santeusanio F. BRAF (V599E) mutation is the leading genetic event in adult sporadic papillary thyroid carcinomas. J Clin Endocrinol Metab. 2004. 89:2414–2420.
17. Namba H, Rubin SA, Fagin JA. Point mutations of ras oncogenes are an early event in thyroid tumorigenesis. Mol Endocrinol. 1990. 4:1474–1479.
18. Sugg SL, Zheng L, Rosen IB, Freeman JL, Ezzat S, Asa S. Ret/PTC-1, -2, and -3 oncogene rearrangements in human thyroid carcinomas: implications for metastatic potential? J Clin Endocrinol Metab. 1996. 81:3360 –3365.
19. Klugbauer S, Lengfelder E, Demidchik EP, Rabes HM. High prevalence of RET rearrangement in thyroid tumors of children from Belarus after the Chernobyl reactor accident. Oncogene. 1995. 11:2459–2467.
20. Fugazzola L, Pierotti MA, Vigano E, Pacini F, Vorontsova TV, Bongarzone I. Molecular and biochemical analysis of RET/PTC4, a novel oncogenic rearrangement between RET and ELE1 genes, in a post-Chernobyl papillary thyroid cancer. Oncogene. 1996. 13:1093–1097.
21. Wajjwalku W, Nakamura S, Hasegawa Y, Miyazaki K, Satoh Y, Funahashi H, Matsuyama M, Takahashi M. Low frequency of rearrangements of the ret and trk proto-oncogenes in Japanese thyroid papillary carcinomas. Jpn J Cancer Res. 1992. 83:671–675.
22. Namba H, Nakashima M, Hayashi T, Hayashida N, Maeda S, Rogounovitch TI, Ohtsuru A, Saenko VA, Kanematsu T, Yamashita S. Clinical implication of hot spot BRAF mutation, V599E, in papillary thyroid cancers. J Clin Endocrinol Metab. 2003. 88:4393–4397.
23. Said S, Schlumberger M, Suarez HG. Oncogenes and anti-oncogenes in human epithelial thyroid tumors. J Endocrinol Invest. 1994. 17:371–379.
24. Shi YF, Zou MJ, Schmidt H, Juhasz F, Stensky V, Robb D, Farid NR. High rates of rascodon 61 mutation in thyroid tumors in an iodide-deficient area. Cancer Res. 1991. 51:2690–2693.
25. Esapa CT, Johnson SJ, Kendall-Taylor P, Lennard TW, Harris PE. Prevalence of Ras mutations in thyroid neoplasia. Clin Endocrinol (Oxf). 1999. 50:529–535.
26. Zhu Z, Gandhi M, Nikiforova MN, Fischer AH, Nikiforov YE. Molecular profile and clinical-pathologic features of the follicular variant of papillary thyroid carcinoma. An unusually high prevalence of ras mutations. Am J Clin Pathol. 2003. 120:71–77.
27. Liu RT, Hou CY, You HL, Huang CC, Hock-Liew , Chou FF, Wang PW, Cheng JT. Selective occurrence of rasmutations in benign and malignant thyroid follicular neoplasms in Taiwan. Thyroid. 2004. 14:616–621.
28. Vasko V, Ferrand M, Di Cristofaro J, Carayon P, Henry JF, de Micco C. Specific pattern of RAS oncogene mutations in follicular thyroid tumors. J Clin Endocrinol Metab. 2003. 88:2745–2752.
29. Naito H, Pairojkul C, Kitahori Y, Yane K, Miyahara H, Konishi N, Matsunaga T, Hiasa Y. Different ras gene mutational frequencies in thyroid papillary carcinomas in Japan and Thailand. Cancer Lett. 1998. 131:171–175.
30. Yoon HJ, Ju JY, Cho GJ, Kim EJ, Park KH, Kim KS, Ko YC, Lim SC, Kim YC, Park KO, Park JT. K-ras gene mutation in non-small cell lung cancer. J Lung Cancer. 2002. 1:55–59.
31. Kim YC, Choi KH, Kim HG, Lee ES, Son GS. Significance of K-ras mutation, K-ras expression and p53 expression in pancreatic cancer. Korean J Hepatobiliary Pancreat Surg. 2000. 4:111–121.
32. Orita M, Sekiya T, Hayashi K. DNA sequence polymorphisms in Alu repeats. Genomics. 1990. 8:271–278.
TOOLS
Similar articles