Application of molecular markers in the diagnostics of thyroid focal lesions – current state of knowledge Review article
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Published:
Jun 29, 2012
Keywords:
thyroid nodular disease, thyroid cancer, fine-needle aspiration biopsy, molecular markers
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Abstract
Thyroid nodular disease is a common disorder and affects about 20% of adult polish population. Due to the fact that methods currently applied in routine assessment of these changes often do not provide accurate diagnosis, the research are ongoing to identify novel markers of malignancy, including molecular ones. Thus far not a single marker was found, which characterises with satisfying sensitivity and specificity in the preoperative differentiation of benign and malignant thyroid lesions. None of the developed potential markers was included to the routine diagnostic procedures or guidelines, either. However, intensive research aiming to search for novel molecular markers, optimization of methods of detection and evaluation of their true clinical utility bring more and more promising results. Analysis of not a single studied marker cannot serve as independent diagnostic method. However, examination of a group of several markers, together with ultrasound examination and classic cytological examination, may contribute to the increase in sensitivity and specificity in detection of malignant lesions and thus, make further therapeutic decisions in a patient with thyroid nodular disease easier.
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Ruchała M, Woliński K, Fularz M, Szczepanek-Parulska E. Application of molecular markers in the diagnostics of thyroid focal lesions – current state of knowledge. OncoReview [Internet]. 2012Jun.29 [cited 2024Jul.3];2(2(6):93-100. Available from: https://journalsmededu.pl/index.php/OncoReview/article/view/302
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Copyright: © Medical Education sp. z o.o. This is an Open Access article distributed under the terms of the Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). License (https://creativecommons.org/licenses/by-nc/4.0/), allowing third parties to copy and redistribute the material in any medium or format and to remix, transform, and build upon the material, provided the original work is properly cited and states its license.
Address reprint requests to: Medical Education, Marcin Kuźma (marcin.kuzma@mededu.pl)
References
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5. Kim D.L., Song K.H., Kim S.K.: High prevalence of carcinoma in ultrasonography-guided fine needle aspiration cytology of thyroid nodules. Endocr. J. 2008; 55: 135-142.
6. Papini E., Guglielmi R., Bianchini A. et al.: Risk of malignancy in nonpalpable thyroid nodules: predictive value of ultrasound and color-Doppler features. J. Clin. Endocrinol. Metab. 2002; 87: 1941-1946.
7. Nikiforov Y.E., Ohori N.P., Hodak S.P. et al.: Impact of mutational testing on the diagnosis and management of patients with cytologically indeterminate thyroid nodules: a prospective analysis of 1056 FNA samples. J. Clin. Endocrinol. Metab. 2011; 96: 3390-3397.
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10. Mazzaferri E.L.: Management of a solitary thyroid nodule. N. Engl. J. Med. 1993; 328: 553-559.
11. Davies H., Bignell G.R., Cox C. et al.: Mutations of the BRAF gene in human cancer. Nature 2002; 417: 949-954.
12. Namba H., Nakashima M., Hayashi T. et al.: Clinical implication of hot spot BRAF mutation, V599E, in papillary thyroid cancers. J. Clin. Endocr. Metab. 2003; 88: 4393-4397.
13. Nucera C., Porrello A., Antonello Z.A. et al.: B-RafV600E and thrombospondin-1 promote thyroid cancer progression. Proc. Natl. Acad. Sci. USA 2010; 107(23): 10649-54.
14. Knauf J.A., Ma X., Smith E.P. et al.: Targeted Expression of BRAFV600E in Thyroid Cells of Transgenic Mice Results in Papillary Thyroid Cancers that Undergo Dedifferentiation. Cancer Res. 2005; 65: 4238-4245.
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23. Garcia-Rostan G., Zhao H., Camp R.L. et al.: Ras mutations are associated with aggressive tumor phenotypes and poor prognosis in thyroid cancer. J. Clin. Oncol. 2003; 21: 3226-35.
24. Di Cristofaro J., Marcy M., Vasko V. et al.: Molecular genetic study comparing follicular variant versus classic papillary thyroid carcinomas: association of N ras mutation in codon 61 with follicular variant. Hum. Pathol. 2006; 37: 824-30.
25. Nikiforova M.N., Lynch R.A., Biddinger P.W. 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: 2318-26.
26. Vasko V., Ferrand M., Di Cristofaro J. et al.: Specific pattern of RAS oncogene mutations in follicular thyroid tumors. J. Clin. Endocrinol. Metab. 2003; 88: 2745-52.
27. Esapa C.T., Johnson S.J., Kendall-Taylor P. et al.: Prevalence of Ras mutations in thyroid neoplasia. Clin. Endocrinol. (Oxf.) 1999; 50: 529-35.
28. Lemoine N.R., Mayall E.S., Wyllie F.S. et al.: High frequency of ras oncogene activation in all stages of human thyroid tumorigenesis. Oncogene 1989; 4: 159-64.
29. Namba H., Rubin S.A., Fagin J.A.: Point mutations of ras oncogenes are an early event in thyroid tumorigenesis. Mol. Endocrinol. 1990; 4: 1474-9.
30. Suarez H.G., du Villard J.A., Severino M. et al.: Presence of mutations in all three ras genes in human thyroid tumors. Oncogene 1990; 5: 565-70.
31. Motoi N., Sakamoto A., Yamochi T. et al.: Role of ras mutation in the progression of thyroid carcinoma of follicular epithelial origin. Pathol. Res. Pract. 2000; 196: 1-7.
32. Manenti G., Pilotti S., Re F.C. et al.: Selective activation of ras oncogenes in follicular and undifferentiated thyroid carcinomas. Eur. J. Cancer 1994; 30A: 987-93.
33. Sciacchitano S., Paliotta D.S., Nardi F. et al.: PCR amplification and analysis of ras oncogenes from thyroid cytologic smears. Diagn. Mol. Pathol. 1994; 3: 114-21.
34. 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: 1161-70.
35. Wang Y., Hou P., Yu H. et al.: High prevalence and mutual exclusivity of genetic alterations in the phosphatidylinositol-3-kinase/akt pathway in thyroid tumors. J. Clin. Endocrinol. Metab. 2007; 92: 2387-90.
36. Wu G., Mambo E., Guo Z. et al.: Uncommon mutation, but common amplifications, of the PIK3CA gene in thyroid tumors. J. Clin. Endocrinol. Metab. 2005; 90: 4688-93.
37. Krysiak R., Marek B., Okopień B.: Rak rdzeniasty tarczycy – aktualny stan wiedzy. Endokrynologia Polska 2008; 59: 446-55.
38. Nikiforov Y.E.: RET/PTC Rearrangement in Thyroid Tumors. Endocr. Pathol. 2002; 13: 3-16.
39. Cheung C.C., Carydis B., Ezzat S. et al.: Analysis of ret/PTC gene rearrangements refines the fine needle aspiration diagnosis of thyroid cancer. J. Clin. Endocrinol. Metab. 2001; 86: 2187-90.
40. Salvatore G., Giannini R., Faviana P. et al.: Analysis of BRAF point mutation and RET/PTC rearrangement refines the fine-needle aspiration diagnosis of papillary thyroid carcinoma. J. Clin. Endocrinol. Metab. 2004; 89: 5175-80.
41. Eberhardt N.L., Grebe S.K., McIver B. et al.: The Role of the PAX8/PPARγ Fusion Oncogene in the Pathogenesis of Follicular Thyroid Cancer. Mol. Cell. Endocrinol. 2010; 321(1): 50-6.
42. Sahin M., Allard B.L., Yates M. et al.: PPARgamma staining as a surrogate for PAX8/PPARgamma fusion oncogene expression in follicular neoplasms: clinicopathological correlation and histopathological diagnostic value. J. Clin. Endocrinol. Metab. 2005; 90(1): 463-8.
43. Marques A.R., Espadinha C., Frias M.J. et al.: Underexpression of peroxisome proliferator-activated receptor (PPAR)g in PAX8/PPARg-negative thyroid tumours. Br. J. Cancer 2004; 91(4): 732-8.
44. Dwight T., Thoppe S.R., Foukakis T. et al.: Involvement of the PAX8/peroxisome proliferator-activated receptor gamma rearrangement in follicular thyroid tumors. J. Clin. Endocrinol. Metab. 2003; 88(9): 4440-5.
44. French C.A., Alexander E.K., Cibas E.S. et al.: Genetic and biological subgroups of low-stage follicular thyroid cancer. Am. J. Pathol. 2003 Apr; 162(4): 1053-60.
45. Cheung L., Messina M., Gill A. et al.: Detection of the PAX8-PPAR gamma fusion oncogene in both follicular thyroid carcinomas and adenomas. J. Clin. Endocrinol. Metab. 2003; 88(1): 354-7.
46. Reddi H.V., Madde P., Milosevic D. et al.: The Putative PAX8/PPARγ Fusion Oncoprotein Exhibits Partial Tumor Suppressor Activity through Up-Regulation of Micro-RNA-122 and Dominant-Negative PPARγ Activity. Genes Cancer 2011; 2(1): 46-55.
47. Baudin E., Do Cao C., Cailleux A.F. et al.: Positive predictive value of serum thyroglobulin levels, measured during the first year of follow-up after thyroid hormone withdrawal, in thyroid cancer patients. J. Clin. Endocrinol. Metab. 2003; 88(3): 1107-11.
48. Savagner F., Rodien P., Reynier P. et al.: Analysis of Tg transcripts by real-time RT-PCR in the blood of thyroid cancer patients. J. Clin. Endocrinol. Metab. 2002; 87(2): 635-9.
49. Wagner K., Arciaga R., Siperstein A. et al.: Thyrotropin receptor/thyroglobulin messenger ribonucleic acid in peripheral blood and fine-needle aspiration cytology: diagnostic synergy for detecting thyroid cancer. J. Clin. Endocrinol. Metab. 2005; 90(4): 1921-4.
50. Milas M., Mazzaglia P., Chia S.Y. et al.: The utility of peripheral thyrotropin mRNA in the diagnosis of follicular neoplasms and surveillance of thyroid cancers. Surgery 2007; 141(2): 137-46.
51. Tischer E., Mitchell R., Hartman et al.: The human gene for vascular endothelial growth factor: multiple protein forms are encoded through alternative exon splicing. J. Biol. Chem. 1991; 266: 11947-11954.
52. Tayama M., Furuhata T., Inafuku Y. et al.: Vascular endothelial growth factor 165b expression in stromal cells and colorectal cancer. World J. Gastroenterol. 2011; 17(44): 4867-74.
53. Lin S.Y., Wang Y.Y., Sheu W.H.: Preoperative plasma concentrations of vascular endothelial growth factor and matrix metalloproteinase 9 are associated with stage progression in papillary thyroid cancer. Clin. Endocrinol. (Oxf.) 2003; 58(4): 513-8.
54. Konturek A., Barczyński M., Cichoń S. et al.: Significance of vascular endothelial growth factor and epidermal growth factor in development of papillary thyroid cancer. Langenbecks Arch. Surg. 2005; 390(3): 216-21.
55. Soh E.Y., Duh Q.Y., Sobhi S.A. et al.: Vascular endothelial growth factor expression is higher in differentiated thyroid cancer than in normal or benign thyroid. J. Clin. Endocrinol. Metab. 1997; 82(11): 3741-7.
56. Salajegheh A., Smith R.A., Kasem K. et al.: Single nucleotide polymorphisms and mRNA expression of VEGF-A in papillary thyroid carcinoma: potential markers for aggressive phenotypes. Eur. J. Surg. Oncol. 2011; 37(1): 93-9.
57. Klein M., Vignaud J.M., Hennequin V. et al.: Increased expression of the vascular endothelial growth factor is a pejorative prognosis marker in papillary thyroid carcinoma. J. Clin. Endocr. Metab. 2001; 86: 656-658.
58. Guittaut M., Charpentier S., Normand T. et al.: Identification of an internal gene to the human galectin-3 gene with two different overlapping reading frames that do not encode galectin-3. J. Biol. Chem. 2001; 276: 2652-2657.
59. Pricci F., Leto G., Amadio L. et al.: Role of galectin-3 as a receptor for advanced glycosylation end products. Kidney Int. Suppl. 2000; 77: 31-9.
60. Nangia-Makker P., Nakahara S., Hogan V. et al.: Galectin-3 in apoptosis, a novel therapeutic target. J. Bioenerg. Biomembr. 2007; 39(1): 79-84.
61. Samija I., Mateša N., Lukač J. et al.: Galectin-3 and CD44v6 as markers for preoperative diagnosis of thyroid cancer by RT-PCR. Diagn. Mol. Pathol. 2011; 20(4): 233-41.
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63. Ersoz S., Sert H., Yandi M. et al.: The significance of Galectin-3 expression in the immunocytochemical evaluation of thyroid fine needle aspiration cytology. Pathol. Oncol. Res. 2008; 14(4): 457-60.
2. Mazzaferri E.L., de los Santos E.T., Rofagha-Keyhani S.: Solitary thyroid nodule: diagnosis and management. Med. Clin. North Am. 1988; 72: 1177-1211.
3. Cooper D.S., Doherty G.M., Haugen B.R. et al.: Management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 2006; 16: 109-142.
4. Frates M.C., Benson C.B., Doubilet P.M. et al.: Prevalence and distribution of carcinoma in patients with solitary and multiple thyroid nodules on sonography. J. Clin. Endocrinol. Metab. 2006; 91: 3411-3417.
5. Kim D.L., Song K.H., Kim S.K.: High prevalence of carcinoma in ultrasonography-guided fine needle aspiration cytology of thyroid nodules. Endocr. J. 2008; 55: 135-142.
6. Papini E., Guglielmi R., Bianchini A. et al.: Risk of malignancy in nonpalpable thyroid nodules: predictive value of ultrasound and color-Doppler features. J. Clin. Endocrinol. Metab. 2002; 87: 1941-1946.
7. Nikiforov Y.E., Ohori N.P., Hodak S.P. et al.: Impact of mutational testing on the diagnosis and management of patients with cytologically indeterminate thyroid nodules: a prospective analysis of 1056 FNA samples. J. Clin. Endocrinol. Metab. 2011; 96: 3390-3397.
8. Baloch Z.W., LiVolsi V.A., Asa S.L. et al.: Diagnostic terminology and morphologic criteria for cytologic diagnosis of thyroid lesions: a synopsis of the National Cancer Institute Thyroid Fine-Needle Aspiration State of the Science Conference. Diagn. Cytopathol. 2008; 36: 425-437.
9. Baloch Z.W., Fleisher S., LiVolsi V.A. et al.: Diagnosis of „follicular neoplasm”: a gray zone in thyroid fine-needle aspiration cytology. Diagn. Cytopathol. 2002; 26: 41-44.
10. Mazzaferri E.L.: Management of a solitary thyroid nodule. N. Engl. J. Med. 1993; 328: 553-559.
11. Davies H., Bignell G.R., Cox C. et al.: Mutations of the BRAF gene in human cancer. Nature 2002; 417: 949-954.
12. Namba H., Nakashima M., Hayashi T. et al.: Clinical implication of hot spot BRAF mutation, V599E, in papillary thyroid cancers. J. Clin. Endocr. Metab. 2003; 88: 4393-4397.
13. Nucera C., Porrello A., Antonello Z.A. et al.: B-RafV600E and thrombospondin-1 promote thyroid cancer progression. Proc. Natl. Acad. Sci. USA 2010; 107(23): 10649-54.
14. Knauf J.A., Ma X., Smith E.P. et al.: Targeted Expression of BRAFV600E in Thyroid Cells of Transgenic Mice Results in Papillary Thyroid Cancers that Undergo Dedifferentiation. Cancer Res. 2005; 65: 4238-4245.
15. Xing M., Tufano R.P., Tufaro A.P. et al.: Detection of BRAF Mutation on Fine Needle Aspiration Biopsy Specimens: A New Diagnostic Tool for Papillary Thyroid Cancer J. Clin. Endocrinol. Metab. 2004; 89(6): 2867-72.
16. Nikiforov Y.E.: Molecular diagnostics of thyroid tumors. Arch. Pathol. Lab. Med. 2011; 135(5): 569-77.
17. Giannini R., Ugolini C., Lupi C. et al.: The Heterogeneous Distribution of BRAF Mutation Supports the Independent Clonal Origin of Distinct Tumor Foci in Multifocal Papillary Thyroid Carcinoma. J. Clin. Endocrinol. Metab. 2007; 92(9): 3511-6.
18. Kumar V., Cotran R., Robbins S.: Patologia. Wydawnictwo Medyczne Urban & Patrner, Wrocław 2005.
19. Nikiforov Y.E., Steward D.L., Robinson-Smith T.M. et al.: Molecular testing for mutations in improving the fine-needle aspiration diagnosis of thyroid nodules. J. Clin. Endocrinol. Metab. 2009; 94: 2092-8.
20. Kimura E.T., Nikiforova M.N., Zhu Z. et al.: 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: 1454-7.
21. Basolo F., Pisaturo F., Pollina L.E. et al.: N-ras mutation in poorly differentiated thyroid carcinomas: correlation with bone metastases and inverse correlation to thyroglobulin expression. Thyroid 2000; 10: 19-23.
22. Zhu Z., Gandhi M., Nikiforova M.N. et al.: 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: 71-7.
23. Garcia-Rostan G., Zhao H., Camp R.L. et al.: Ras mutations are associated with aggressive tumor phenotypes and poor prognosis in thyroid cancer. J. Clin. Oncol. 2003; 21: 3226-35.
24. Di Cristofaro J., Marcy M., Vasko V. et al.: Molecular genetic study comparing follicular variant versus classic papillary thyroid carcinomas: association of N ras mutation in codon 61 with follicular variant. Hum. Pathol. 2006; 37: 824-30.
25. Nikiforova M.N., Lynch R.A., Biddinger P.W. 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: 2318-26.
26. Vasko V., Ferrand M., Di Cristofaro J. et al.: Specific pattern of RAS oncogene mutations in follicular thyroid tumors. J. Clin. Endocrinol. Metab. 2003; 88: 2745-52.
27. Esapa C.T., Johnson S.J., Kendall-Taylor P. et al.: Prevalence of Ras mutations in thyroid neoplasia. Clin. Endocrinol. (Oxf.) 1999; 50: 529-35.
28. Lemoine N.R., Mayall E.S., Wyllie F.S. et al.: High frequency of ras oncogene activation in all stages of human thyroid tumorigenesis. Oncogene 1989; 4: 159-64.
29. Namba H., Rubin S.A., Fagin J.A.: Point mutations of ras oncogenes are an early event in thyroid tumorigenesis. Mol. Endocrinol. 1990; 4: 1474-9.
30. Suarez H.G., du Villard J.A., Severino M. et al.: Presence of mutations in all three ras genes in human thyroid tumors. Oncogene 1990; 5: 565-70.
31. Motoi N., Sakamoto A., Yamochi T. et al.: Role of ras mutation in the progression of thyroid carcinoma of follicular epithelial origin. Pathol. Res. Pract. 2000; 196: 1-7.
32. Manenti G., Pilotti S., Re F.C. et al.: Selective activation of ras oncogenes in follicular and undifferentiated thyroid carcinomas. Eur. J. Cancer 1994; 30A: 987-93.
33. Sciacchitano S., Paliotta D.S., Nardi F. et al.: PCR amplification and analysis of ras oncogenes from thyroid cytologic smears. Diagn. Mol. Pathol. 1994; 3: 114-21.
34. 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: 1161-70.
35. Wang Y., Hou P., Yu H. et al.: High prevalence and mutual exclusivity of genetic alterations in the phosphatidylinositol-3-kinase/akt pathway in thyroid tumors. J. Clin. Endocrinol. Metab. 2007; 92: 2387-90.
36. Wu G., Mambo E., Guo Z. et al.: Uncommon mutation, but common amplifications, of the PIK3CA gene in thyroid tumors. J. Clin. Endocrinol. Metab. 2005; 90: 4688-93.
37. Krysiak R., Marek B., Okopień B.: Rak rdzeniasty tarczycy – aktualny stan wiedzy. Endokrynologia Polska 2008; 59: 446-55.
38. Nikiforov Y.E.: RET/PTC Rearrangement in Thyroid Tumors. Endocr. Pathol. 2002; 13: 3-16.
39. Cheung C.C., Carydis B., Ezzat S. et al.: Analysis of ret/PTC gene rearrangements refines the fine needle aspiration diagnosis of thyroid cancer. J. Clin. Endocrinol. Metab. 2001; 86: 2187-90.
40. Salvatore G., Giannini R., Faviana P. et al.: Analysis of BRAF point mutation and RET/PTC rearrangement refines the fine-needle aspiration diagnosis of papillary thyroid carcinoma. J. Clin. Endocrinol. Metab. 2004; 89: 5175-80.
41. Eberhardt N.L., Grebe S.K., McIver B. et al.: The Role of the PAX8/PPARγ Fusion Oncogene in the Pathogenesis of Follicular Thyroid Cancer. Mol. Cell. Endocrinol. 2010; 321(1): 50-6.
42. Sahin M., Allard B.L., Yates M. et al.: PPARgamma staining as a surrogate for PAX8/PPARgamma fusion oncogene expression in follicular neoplasms: clinicopathological correlation and histopathological diagnostic value. J. Clin. Endocrinol. Metab. 2005; 90(1): 463-8.
43. Marques A.R., Espadinha C., Frias M.J. et al.: Underexpression of peroxisome proliferator-activated receptor (PPAR)g in PAX8/PPARg-negative thyroid tumours. Br. J. Cancer 2004; 91(4): 732-8.
44. Dwight T., Thoppe S.R., Foukakis T. et al.: Involvement of the PAX8/peroxisome proliferator-activated receptor gamma rearrangement in follicular thyroid tumors. J. Clin. Endocrinol. Metab. 2003; 88(9): 4440-5.
44. French C.A., Alexander E.K., Cibas E.S. et al.: Genetic and biological subgroups of low-stage follicular thyroid cancer. Am. J. Pathol. 2003 Apr; 162(4): 1053-60.
45. Cheung L., Messina M., Gill A. et al.: Detection of the PAX8-PPAR gamma fusion oncogene in both follicular thyroid carcinomas and adenomas. J. Clin. Endocrinol. Metab. 2003; 88(1): 354-7.
46. Reddi H.V., Madde P., Milosevic D. et al.: The Putative PAX8/PPARγ Fusion Oncoprotein Exhibits Partial Tumor Suppressor Activity through Up-Regulation of Micro-RNA-122 and Dominant-Negative PPARγ Activity. Genes Cancer 2011; 2(1): 46-55.
47. Baudin E., Do Cao C., Cailleux A.F. et al.: Positive predictive value of serum thyroglobulin levels, measured during the first year of follow-up after thyroid hormone withdrawal, in thyroid cancer patients. J. Clin. Endocrinol. Metab. 2003; 88(3): 1107-11.
48. Savagner F., Rodien P., Reynier P. et al.: Analysis of Tg transcripts by real-time RT-PCR in the blood of thyroid cancer patients. J. Clin. Endocrinol. Metab. 2002; 87(2): 635-9.
49. Wagner K., Arciaga R., Siperstein A. et al.: Thyrotropin receptor/thyroglobulin messenger ribonucleic acid in peripheral blood and fine-needle aspiration cytology: diagnostic synergy for detecting thyroid cancer. J. Clin. Endocrinol. Metab. 2005; 90(4): 1921-4.
50. Milas M., Mazzaglia P., Chia S.Y. et al.: The utility of peripheral thyrotropin mRNA in the diagnosis of follicular neoplasms and surveillance of thyroid cancers. Surgery 2007; 141(2): 137-46.
51. Tischer E., Mitchell R., Hartman et al.: The human gene for vascular endothelial growth factor: multiple protein forms are encoded through alternative exon splicing. J. Biol. Chem. 1991; 266: 11947-11954.
52. Tayama M., Furuhata T., Inafuku Y. et al.: Vascular endothelial growth factor 165b expression in stromal cells and colorectal cancer. World J. Gastroenterol. 2011; 17(44): 4867-74.
53. Lin S.Y., Wang Y.Y., Sheu W.H.: Preoperative plasma concentrations of vascular endothelial growth factor and matrix metalloproteinase 9 are associated with stage progression in papillary thyroid cancer. Clin. Endocrinol. (Oxf.) 2003; 58(4): 513-8.
54. Konturek A., Barczyński M., Cichoń S. et al.: Significance of vascular endothelial growth factor and epidermal growth factor in development of papillary thyroid cancer. Langenbecks Arch. Surg. 2005; 390(3): 216-21.
55. Soh E.Y., Duh Q.Y., Sobhi S.A. et al.: Vascular endothelial growth factor expression is higher in differentiated thyroid cancer than in normal or benign thyroid. J. Clin. Endocrinol. Metab. 1997; 82(11): 3741-7.
56. Salajegheh A., Smith R.A., Kasem K. et al.: Single nucleotide polymorphisms and mRNA expression of VEGF-A in papillary thyroid carcinoma: potential markers for aggressive phenotypes. Eur. J. Surg. Oncol. 2011; 37(1): 93-9.
57. Klein M., Vignaud J.M., Hennequin V. et al.: Increased expression of the vascular endothelial growth factor is a pejorative prognosis marker in papillary thyroid carcinoma. J. Clin. Endocr. Metab. 2001; 86: 656-658.
58. Guittaut M., Charpentier S., Normand T. et al.: Identification of an internal gene to the human galectin-3 gene with two different overlapping reading frames that do not encode galectin-3. J. Biol. Chem. 2001; 276: 2652-2657.
59. Pricci F., Leto G., Amadio L. et al.: Role of galectin-3 as a receptor for advanced glycosylation end products. Kidney Int. Suppl. 2000; 77: 31-9.
60. Nangia-Makker P., Nakahara S., Hogan V. et al.: Galectin-3 in apoptosis, a novel therapeutic target. J. Bioenerg. Biomembr. 2007; 39(1): 79-84.
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