• 2014
  • 2013
  • 2012
  • 2011
  • 2010
  • 2009
  • 2008

The journal «ONCOSURGERY» 2013, Vol.5, No 2

Molecular genetic studies for planning of surgical treatment and chemotherapy for thyroid cancer

Reshetov IV3, Golubtsov АК3, Abramov АА1,2, Belokhvostov АS1,2, Gorjunkov АG4, Krekhno ОP3

1) Research Practical Centre of Medical Care for Children,
2) Federal Research and Clinical Centre of Pediatric Hematology, Oncology and Immunology,
3) PA Herzen Moscow Cancer Research Institute,
4) Post graduate Institute of Federal Medico-Biological Agency,
Moscow, Russia
Contact: Goryunkov Aleksey Grigorjevich, e-mail:

The results of molecular genetic studies conducted by different study groups and assessing the prospects for analysis of molecular and genetic markers in patients with different types of thyroid cancer are represented.

Gene mutations for thyroid cancer. The analysis of literature data on molecular and genetic defects for thyroid cancer was performed showing prognostic and diagnostic value of such molecular and genetic markers as gene BRAF, KRAS, RET, and others, involved in pathogenesis of thyroid cancer. These studies examined the possibility for analysis of hotspots mutations in BRAF and RET for planning the surgical treatment and gene RAS analysis for determination of early tissue malignant transformation.

Results of own study were represented, they correlated with world literature data. The investigation of biological material was shown to be feasible both for tumor specimen and biological fluids (blood plasma, saliva). Analysis of molecular and genetic markers, such as BRAF, KRAS and TP53, was performed.

Conclusion. The capability of molecular genetic analysis allows to use selective approach to treatment of patients with different types of thyroid cancer. Analysis of genetic changes in cancer cells allows to reduce risk of surgical complications, decrease recurrence and metastasis rates, to actualize the person-oriented approach to chemo- and radiotherapy. New therapeutic strategies, based on different molecular mechanisms, make the personalized targeted therapy to be possible.

KEY WORDS: molecular genetic studies, markers, mytations.

References

  1. Nikiforov YE. Molecular diagnostics of thyroid tumors. Arch Pathol Lab Med .2011; 135: 569-77.
  2. Adeniran AJ, Zhu Z, Gandhi M, et al. Correlation between genetic alterations and microscopic features, clinical manifestations, and prognostic characteristics of thyroid papillary carcinomas. Am J Surg Pathol. 2006; 30(2): 216-22.
  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. Soares P, Trovisco V, Rocha AS, et al. BRAF mutations and RET/PTC rearrangements are alternative events in the etiopathogenesis of PTC. Oncogene. 2003; 22(29): 4578-80.
  5. Frattini M, Ferrario C, Bressan P, et al. Alternative mutations of BRAF, RET and NTRK1 are associated with similar but distinct gene expression patterns in papillary thyroid cancer. Oncogene. 2004; 23(44): 7436-40.
  6. Nikiforova MN, Lynch RA, Biddinger PW, et al. RAS point mutations and PAX8-PPAR gamma rearrangement in thyroid tumors: evidence for distinct molecular pathways in thyroid follicular carcinoma. J Clin Endocrinol Metab. 2003; 88(5): 2318-26.
  7. Garcia-Rostan G, Costa AM, Pereira-Castro I, et al. Mutation of the PIK3CA gene in anaplastic thyroid cancer. Cancer Res. 2005; 65(22): 10199-207.
  8. Hou P, Liu D, Shan Y, et al. Genetic alterations and their relationship in the phosphatidylinositol 3-kinase/Akt pathway in thyroid cancer. Clin Cancer Res. 2007; 13(4): 1161-70.
  9. Ricarte-Filho JC, Ryder M, Chitale DA, et al. Mutational profile of advanced primary and metastatic radioactive iodine-refractory thyroid cancers reveals distinct pathogenetic roles for BRAF, PIK3CA, and AKT1. Cancer Res. 2009; 69(11): 4885-93.
  10. Kondo T, Ezzat S, Asa SL. Pathogenetic mechanisms in thyroid follicularcell neoplasia. Nat Rev Cancer. 2006; 6(4): 292-306.
  11. de Groot JW, Links TP, Plukker JT, Lips CJ, Hofstra RM. RET as a diagnostic and therapeutic target in sporadic and hereditary endocrine tumors. Endocr Rev. 2006; 27(5): 535-60.
  12. 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.
  13. Cohen Y, Xing M, Mambo E, et al. BRAF mutation in papillary thyroid carcinoma. J Natl Cancer Inst. 2003; 95(8): 625–7.
  14. Xing M. BRAF mutation in thyroid cancer. Endocr Relat Cancer. 2005; 12(2): 245–62.
  15. Ciampi R, Nikiforov YE. Alterations of the BRAF gene in thyroid tumors. Endocr Pathol. 2005; 16(3): 163–72.
  16. Wan PT, Garnett MJ, Roe SM, et al. Mechanism of activation of the RAFERK signaling pathway by oncogenic mutations of B-RAF. Cell 2004; 116(6): 855–67.
  17. Knauf JA, Ma X, Smith EP, et al. Targeted expression of BRAFV600E in thyroid cells of transgenic mice results in papillary thyroid cancers that undergo dedifferentiation. Cancer Res 2005; 65(10): 4238–45.
  18. Trovisco V, Vieira de Castro I, Soares P, et al. BRAF mutations are associated with some histological types of papillary thyroid carcinoma. J Pathol. 2004; 202(2): 247–51.
  19. Carta C, Moretti S, Passeri L, et al. Genotyping of an Italian papillary thyroid carcinoma cohort revealed high prevalence of BRAF mutations, absence of RAS mutations and allowed the detection of a new mutation of BRAF oncoprotein (BRAF(V599lns)). Clin Endocrinol (Oxf). 2006; 64(1): 105–9.
  20. Hou P, Liu D, Xing M. Functional characterization of the T1799-1801del and A1799-1816ins BRAF mutations in papillary thyroid cancer. Cell Cycle. 2007;6(3):377–379.
  21. Chiosea S, Nikiforova M, Zuo H, et al. A novel complex BRAF mutation detected in a solid variant of papillary thyroid carcinoma. Endocr Pathol. 2009; 20(2): 122–6.
  22. Basolo F, Torregrossa L, Giannini R, et al. Correlation between the BRAF V600E mutation and tumor invasiveness in papillary thyroid carcinomas smaller than 20 millimeters: analysis of 1060 cases. J Clin Endocrinol Metab. 2010; 95(9): 4197–205.
  23. Nikiforova MN, Nikiforov YE. Molecular diagnostics and predictors in thyroid cancer. Thyroid. 2009; 19(12): 1351–61.
  24. Nikiforov YE, Steward DL, Robinson-Smith TM, et al. Molecular testing for mutations in improving the fine-needle aspiration diagnosis of thyroid nodules. J Clin Endocrinol Metab. 2009; 94(6): 2092–8.
  25. Pizzolanti G, Russo L, Richiusa P, et al. Fine-needle aspiration molecular analysis for the diagnosis of papillary thyroid carcinoma through BRAF V600E mutation and RET/PTC rearrangement. Thyroid. 2007; 17(11): 1109–15.
  26. Jo YS, Huang S, Kim YJ, et al. Diagnostic value of pyrosequencing for the BRAF V600E mutation in ultrasound-guided fine-needle aspiration biopsy samples of thyroid incidentalomas. Clin Endocrinol (Oxf). 2009; 70(1): 139–44.
  27. Cohen Y, Rosenbaum E, Clark DP, et al. Mutational analysis of BRAF in fine needle aspiration biopsies of the thyroid: A potential application for the preoperative assessment of thyroid nodules. Clin Cancer Res. 2004;10:2761–2765.
  28. Basolo F, Torregrossa L, at al. Correlation between the BRAF V600E Mutation and Tumor Invasiveness in Papillary Thyroid Carcinomas Smaller than 20 Millimeters: Analysis of 1060 Cases Biostatistics Research Unit (M.M., A.B.), and Endocrinology (R.E., P.V.), University of Pisa, 56126 Pisa, Italy.
  29. Prognostic Utility of BRAF Mutation in Papillary Thyroid Cancer Mingzhao Xing Mol Cell Endocrinol. Author manuscript; available in PMC. 2011 May 28.
  30. Namba H, Rubin SA, Fagin JA. Point mutations of ras oncogenes are an early event in thyroid tumorigenesis. Mol Endocrinol 1990; 4(10): 1474–9.
  31. Karga H, Lee JK, Vickery AL Jr, Thor A, Gaz RD, Jameson JL. Ras oncogene mutations in benign and malignant thyroid neoplasms. J Clin Endocrinol Metab. 1991; 3(4): 832–6.
  32. 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(6): 1010–6.
  33. Basolo F, Pisaturo F, Pollina LE, et al. N-ras mutation in poorly differentiated thyroid carcinomas: correlation with bone metastases and inverse correlation to thyroglobulin expression. Thyroid. 2000; 10(1): 19–23.
  34. Ezzat S, Zheng L, Kolenda J, Safarian A, Freeman JL, Asa SL. Prevalence of activating ras mutations in morphologically characterized thyroid nodules. Thyroid. 1996; 6(5): 409–16.
  35. Vasko VV, Gaudart J, Allasia C, et al. Thyroid follicular adenomas may display features of follicular carcinoma and follicular variant of papillary carcinoma. Eur J Endocrinol. 2004; 151(6): 779–86.
  36. 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(1): 71–7.
  37. Lemoine NR, Mayall ES, Wyllie FS, et al. High frequency of ras oncogene activation in all stages of human thyroid tumorigenesis. Oncogene. 1989; 4(2): 159–64.
  38. Suarez HG, du Villard JA, Severino M, et al. Presence of mutations in all three ras genes in human thyroid tumors. Oncogene. 1990; 5(4): 565–70.
  39. Esapa CT, Johnson SJ, Kendall-Taylor P, Lennard TW, Harris PE. Prevalence of ras mutations in thyroid neoplasia. Clin Endocrinol (Oxf). 1999; 50(4): 529–35.
  40. Motoi N, Sakamoto A, Yamochi T, Horiuchi H, Motoi T, Machinami R. Role of ras mutation in the progression of thyroid carcinoma of follicular epithelial origin. Pathol Res Pract. 2000; 196(1): 1–7.
  41. Lemoine NR, Mayall ES, Wyllie FS, et al. Activated ras oncogenes in human thyroid cancers. Cancer Res. 1988; 48(16): 4459–63. Int J Mol Sci 2012; 13: 221-39. doi: 10.3390/ijms13010221.
  42. Ceolin L, Siqueira DR, et al. Molecular basis of medullary thyroid carcinoma: The role of RET polymorphisms. Int J Molecular Sciences, ISSN 1422-0067. Int J Mol Sci 2012, 13:221-239.
  43. Salehian B, Samoa R. RET Gene Abnormalities and Thyroid Disease: Who Should be Screened and When City of Hope Department of Diabetes, Endocrine & Metabolism, California, USA. J Clin Res Pediatr Endocrinol. 2013; 5 Suppl 1:70-8.
  44. Elisei R, Cosci B, et al. Prognostic Significance of Somatic RET Oncogene Mutations in Sporadic Medullary Thyroid Cancer: A 10-Year Follow-Up Study 2008 Mar: 93(3): 682-7.
  45. Romei C, Ugolini C, et al. Low prevalence of the somatic M918T RET mutation in micro-medullary thyroid cancer. Thyroid. 2012 May; 22(5): 476-81.

P. 6-11

Publishers
«Oncokhirurgia Info»

10 Vostochnaia ul., suite 16, Moscow, 115280
Tel./fax: +7(499) 426-46-22
Tel.: +7(915) 356-03-07
E-mail:
URL: oncosurgery.oncology.ru


РСХО