The Effect of BRAF T1799A Mutation on Tumor Size of Papillary Thyroid Cancer

Abstract

Objective: The incidence of thyroid cancer, the most common endocrine malignancy isincreasing in all populations. Papillary thyroid cancer constitutes approximatelly 80 % of thethyroid cancers and several BRAF gene mutations escpecially T1799A are involved in theetiology of papillary thyroid cancer. The aim of this study was to investigate the frequency ofBRAF T1799A mutation in thyroid cancer and the possible association between BRAFT1799A mutation and tumor size.Methods: The study was conducted with 58 cases with thyroid cancer and 52 cases with nocancer in totally 108 cases. DNA isolated from paraffin-embedded tissues of cases, and thegenotypes were analyzed by PCR-RFLP method. Statistical analyses were performed usingSPSS 17.0 software. P values less than 0.05 were accepted as statistically significant.Results: There was no statistically significant association between patient and control groupsin term of the AA genotype. However TA genotype was significantly higher in patient groupthan control group (p=0.0001, OR=7.089 (2.7-18.6)). When comparing less and more than 1cm tumor size groups in papillary thyroid cancer cases, there was no statistically significantassociation for TA genotype (p=0,51, OR=0,641 (0,1-2,4)) and AA genotype (p=0,67,OR=0,694 (0,1-3,8)).Conclusion: Thyroid cancer has the most increasing rate among all cancers types in the world.So, the elucidation of the molecular basis in detail has gained the great importance. In thisstudy, it was concluded that BRAF T1799A mutation has no effect on tumor size. However,this study should be repeated with larger population to get more confident results

Keywords

• Papillary throid cancer,BRAF,tumor size

Papiller Tiroid Kanserinde Braf T1799a Mutasyonunun Tümör Büyüklüğüne Etkisi

Abstract

Amaç: Tiroid kanseri en yaygın endokrin malinitesidir ve tüm dünyada insidansı giderekartmaktadır. Tüm tiroid kanseri vakalarının yaklaşık % 80’ini teşkil eden papiller tiroidkanserinin etyolojisinde başta T1799A mutasyonu olmak üzere birçok BRAF genmutasyonlarının yer aldığı bilinmektedir. Bu çalışmanın amacı BRAF T1799A mutasyonuntiroid kanserindeki frekansı ve tümör büyüklüğü ile muhtemel ilişkisini araştırmaktır.Gereç ve Yöntem: Çalışmaya tiroid kanseri tanısı konmuş 58 olgu ve kanserden başkasebeplerle opere edilmiş 52 olgu olmak üzere toplam 108 olgu dahil edilmiştir. Olgularınparafine gömülü dokularından DNA izole edilerek genotipleme PCR-RFLP yöntemiyle analizedilmiştir. İstatistiksel analizler SPSS 17.0 programı kullanılarak yapılmıştır. 0,05’ten küçükp değerleri anlamlı olarak kabul edilmiştir.Bulgular: Tiroid kanseri ile kontrol grupları arasında AA genotipi açısından istatistiksel biranlam bulunamazken TA genotipi açısından istatistiksel olarak anlamlı bir ilişki tespit edildi(p=0,0001, OR=7,089 (2,7-18,6)). Tümör boyutu 1 cm’den küçük ve büyük olan papiller tiroidkanseri grupları arasında hem TA genotipi (p=0,51, OR=0,641 (0,1-2,4)) hem de AA genotipi(p=0,67, OR=0,694 (0,1-3,8)) açısından istatistiksel olarak anlamlı bir ilişki bulunamadı.Sonuç: Tiroid kanseri diğer kanser türleri arasında en fazla artış hızına sahip olduğundanmoleküler temelinin aydınlatılması önem kazanmıştır. Yapılan bu çalışmada en yaygın görülenBRAF T1799A mutasyonun tümör büyüklüğüne etkisinin olmadığı sonucuna varılmıştır. Fakatdaha net sonuçlar alabilmek için çalışma daha büyük popülasyonlarda tekrarlanmalıdır

Keywords

• Papiller tiroid kanseri,BRAF,tümör boyutu

References

1. 1. Karabulutlu EY, Bilici M, Cayir K, Tekin SB, Kantarci R. Coping, Anxiety and Depression in Turkish Patients with cancer. Eur J of Gen Med 2010; 7: 296-302.
2. 2. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011; 61): 69-90.
3. 3. Pazaitou-Panayiotou K, Polyzos SA, Mantzoros CS. Obesity and thyroid cancer: epidemiologic associations and underlying mechanisms. Obes Rev. 2013 Aug 28. doi: 10.1111/obr.12070. [Epub ahead of print]
4. 4. Xing M. Prognostic utility of BRAF mutation in papillary thyroid cancer. Mol Cell Endocrinol 2010; 321(1): 86-93.
5. 5. Li Y, Nakamura M, Kakudo K. Targeting of the BRAF gene in papillary thyroid carcinoma (review). Oncol Rep 2009; 22(4): 671-81.
6. 6. Legakis I, Syrigos K. Recent advances in molecular diagnosis of thyroid cancer. J Thyroid Res 2011; 2011: 384213.
7. 7. Witt RL, Ferris RL, Pribitkin EA, Sherman SI, Steward DL, Nikiforov YE. Diagnosis and management of differentiated thyroid cancer using molecular biology. Laryngoscope 2013; 123(4): 1059-64.
8. 8. Davies H, Bignell GR, Cox C, et.al. Mutations of the BRAF gene in human cancer. Nature. 2002; 417(6892):949-54.

9. 9. Pakneshan S, Salajegheh A, Smith RA, Lam AK. Clinicopathological relevance of BRAF mutations in human cancer. Pathology 2013; 45(4):346-56.
10. 10. Espinosa AV, Porchia L, Ringel MD. Targeting BRAF in thyroid cancer. Br J Cancer 2007; 96(1):16-20.
11. 11. Nikiforov YE. Molecular analysis of thyroid tumors. Mod Pathol 2011; 24 Suppl 2: S34-43.
12. 12. Kumagai A, Namba H, Akanov Z, Saenko VA, Meirmanov S, Ohtsuru A, Yano H, Maeda S, Anami M, Hayashi T, Ito M, Sagandikova S, Eleubaeva Z, Mussinov D, Espenbetova M, Yamashita S. Clinical implications of pre-operative rapid BRAF analysis for papillary thyroid cancer. Endocr J 2007; 54(3): 399-405.
13. 13. Nucera C, Lawler J, Hodin R, Parangi S. The BRAFV600E mutation: what is it really orchestrating in thyroid cancer? Oncotarget 2010; 1(8): 751-6.
14. 14. Lloyd R, De Lellis R, Heitz P, Eng C. World Health Organization classification of tumours: pathology and genetics of tumours of the endocrine organs. Lyon, France: IARC Press International Agency for Research on Cancer; 2004.
15. 15. Renshaw AA. Papillary carcinoma of the thyroid
16. 16. Frasca F, Nucera C, Pellegriti G, Gangemi P, Attard M, Stella M, Loda M, Vella V, Giordano C, Trimarchi F, Mazzon E, Belfiore A, Vigneri R. BRAF(V600E) mutation and the biology of papillary thyroid cancer. Endocr Relat Cancer 2008; 15(1): 191-205.
17. 17. Yamak N, Yaykasli KO, Soğuktaş H, Yaykaşlı E, Oktay M, Erdem H, Kaya E, Ekinci A, Kaya S, Kurman Y. Mide Kanseri Hastalarda Survivin Gen Polimorfizminin Araştırılması. Dicle Tıp Dergisi 2012; 39(4):499-503.
18. 18. Powell N, Jeremiah S, Morishita M, Dudley E, Bethel J, Bogdanova T, Tronko M, Thomas G. Frequency of BRAF T1796A mutation in papillary thyroid carcinoma relates to age of patient at diagnosis and not to radiation exposure. J Pathol 2005; 205(5):558-64.
19. 19. Schulten HJ, Salama S, Al-Mansouri Z, Alotibi R, Al-Ghamdi K, Al-Hamour OA, Sayadi H, Al-Aradati H, Al-Johari A, Huwait E, Gari M, Al-Qahtani MH, Al-Maghrabi J. BRAF mutations in thyroid tumors from an ethnically diverse group. Hered Cancer Clin Pract 2012; 10(1): 10.
20. 20. Cohen Y, Xing M, Mambo E, Guo Z, Wu G, Trink B, Beller U, Westra WH, Ladenson PW, Sidransky D. BRAF mutation in papillary thyroid carcinoma. J Natl Cancer Inst 2003; 95(8): 625-7.
21. 21. Rubinstein JC, Sznol M, Pavlick AC, Ariyan S, Cheng E, Bacchiocchi A, Kluger HM, Narayan D, Halaban R. Incidence of the V600K mutation among melanoma patients with BRAF mutations, and potential therapeutic response to the specific BRAF inhibitor PLX4032. J Transl Med 2010; 8: 67.
22. 22. De Falco V, Giannini R, Tamburrino A, Ugolini C, Lupi C, Puxeddu E, Santoro M, Basolo F. Functional characterization of the novel T599I-VKSRdel BRAF mutation in a follicular variant papillary thyroid carcinoma. J Clin Endocrinol Metab 2008; 93(11): 4398-402.
23. 23. Nam SY, Han BK, Ko EY, Kang SS, Hahn SY, Hwang JY, Nam MY, Kim JW, Chung JH, Oh YL, Shin JH. BRAF V600E mutation analysis of thyroid nodules needle aspirates in relation to their ultrasongraphic classification: a potential guide for selection of samples for molecular analysis. Thyroid 2010; 20(3):273-9.
24. 24. Xing M. BRAF mutation in papillary thyroid cancer: pathogenic role, molecular bases, and clinical implications. Endocr Rev 2007; 28(7): 742-62.
25. 25. 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 lowrisk patients with conventional papillary thyroid carcinoma. Clin Endocrinol (Oxf). 2006; 65(3): 364-8.
26. 26.Jo YS, Li S, Song JH, Kwon KH, Lee JC, Rha SY, Lee HJ, Sul JY, Kweon GR, Ro HK, Kim JM, Shong M. Influence of the BRAF V600E mutation on expression of vascular endothelial growth factor in papillary thyroid cancer. J Clin Endocrinol Metab 2006; 91(9): 3667-70.
27. 27. Xing M, Westra WH, Tufano RP, Cohen Y, Rosenbaum E, Rhoden KJ, Carson KA, Vasko V, Larin A, Tallini G, Tolaney S, Holt EH, Hui P, Umbricht CB, Basaria S, Ewertz M, Tufaro AP, Califano JA, Ringel MD, Zeiger MA, Sidransky D, Ladenson PW. BRAF mutation predicts a poorer clinical prognosis for papillary thyroid cancer. J Clin Endocrinol Metab 2005; 90(12): 6373-9.
28. 28. Kurtulmus N, Duren M, Ince U, Cengiz Yakicier M, Peker O, Aydın O, Altiok E, Giray S, Azizlerli H. BRAF(V600E) mutation in Turkish patients with papillary thyroid cancer: strong correlation with indicators of tumor aggressiveness. Endocrine 2012; 42(2): 404-10.
29. 29. Kim TY, Kim WB, Song JY, Rhee YS, Gong G, Cho YM, Kim SY, Kim SC, Hong SJ, Shong YK. The BRAF mutation is not associated with poor prognostic factors in Korean patients with conventional papillary thyroid microcarcinoma. Clin Endocrinol (Oxf) 2005; 63(5): 588-93.