Abstract
The implications of global DNA hypomethylation were recently reported in several models of tumorigenesis. Little is known about this epigenetic event in thyroid neoplasia. The study aimed to evaluate the status of global DNA methylation in several types of thyroid tumors using a monoclonal antibody specific for 5-methylcytidine (5-mc) and to define the diagnosis potential of this marker. 5-mc immunostaining scores were calculated in 17 papillary thyroid carcinomas (PTC), 6 follicular thyroid carcinomas (FTC), 16 follicular adenomas (FA), 19 nodular goiters (NG) and ten Hürthle cells adenomas (HCA). The expression of galectin-3 was also evaluated. Computerized image analysis showed a significant lower level of 5-mc immunostaining in thyroid carcinoma when compared with benign tumors or adjacent normal thyroid parenchyma (P<0.0001). Overall, 5-mc accuracy to distinguish malign from benign thyroid tumors was similar to that of galectin-3 (89% versus 87%, P>0.05). The combination of 5-mc with galectin-3 led to an excellent accuracy level of 96%. Among follicular neoplasia 5-mc accuracy to differentiate malign tumors trends to be higher than galectin-3 one (90% versus 66%, P=0.06). These data stress the necessity of epigenetic events evaluation among thyroid nodules and propose global DNA methylation assessment as a potential diagnostic tool to combine with other valuable markers.
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Aratake Y, Umeki K, Kiyoyama K, Hinoura Y, Sato S, Ohno A, Kuribayashi T, Hirai K, Nabeshima K, Kotani T (2002) Diagnostic utility of galectin-3 and CD26/DPPIV as preoperative diagnostic markers for thyroid nodules. Diagn Cytopathol 26:366–372
Baloch ZW, Fleisher S, LiVolsi VA, Gupta PK (2002) Diagnosis of “follicular neoplasm”: a gray zone in thyroid fine-needle aspiration cytology. Diagn Cytopathol 26:41–44
Bartolazzi A, Gasbarri A, Papotti M, Bussolati G, Lucante T, Khan A, Inohara H, Marandino F, Orlandi F, Nardi F, Vecchione A, Tecce R, Larsson O (2001) Application of an immunodiagnostic method for improving preoperative diagnosis of nodular thyroid lesions. Lancet 357:1644–1650
Bartolazzi A, Papotti M, Orlandi F (2003) Methodological considerations regarding the use of galectin-3 expression analysis in preoperative evaluation of thyroid nodules. J Clin Endocrinol Metab 88:950; author reply 950–951
Beesley MF, McLaren KM (2002) Cytokeratin 19 and galectin-3 immunohistochemistry in the differential diagnosis of solitary thyroid nodules. Histopathology 41:236–243
Bernet VJ, Anderson J, Vaishnav Y, Solomon B, Adair CF, Saji M, Burman KD, Burch HB, Ringel MD (2002) Determination of galectin-3 messenger ribonucleic Acid overexpression in papillary thyroid cancer by quantitative reverse transcription-polymerase chain reaction. J Clin Endocrinol Metab 87:4792–4796
Boltze C, Schneider-Stock R, Quednow C, Hinze R, Mawrin C, Hribaschek A, Roessner A, Hoang-Vu C (2003) Silencing of the maspin gene by promoter hypermethylation in thyroid cancer. Int J Mol Med 12:479–484
Boltze C, Zack S, Quednow C, Bettge S, Roessner A, Schneider-Stock R (2003) Hypermethylation of the CDKN2/p16INK4A promotor in thyroid carcinogenesis. Pathol Res Pract 199:399–404
Buchs AE, Zehavi S, Sher O, Yeheskely E, Muggia-Sulam M, Sherman Y, Rapoport MJ (2003) Heparanase, galectin-3, and tissue factor mRNA are expressed in benign neoplasms of the thyroid. Endocrine 22:81–84
Casey MB, Lohse CM, Lloyd RV (2003) Distinction between papillary thyroid hyperplasia and papillary thyroid carcinoma by immunohistochemical staining for cytokeratin 19, galectin-3, and HBME-[1] Endocr Pathol 14:55–60
Chow LS, Gharib H, Goellner JR, van Heerden JA (2001) Nondiagnostic thyroid fine-needle aspiration cytology: management dilemmas. Thyroid 11:1147–1151
Cravo M, Pinto R, Fidalgo P, Chaves P, Gloria L, Nobre-Leitao C, Costa Mira F (1996) Global DNA hypomethylation occurs in the early stages of intestinal type gastric carcinoma. Gut 39:434–438
de Capoa A, Grappelli C, Volpino P, Bononi M, Musolino A, Ciardi A, Cavallaro A, Cangemi V (2004) Nuclear methylation levels in normal and cancerous thyroid cells. Anticancer Res 24:1495–1500
Feilchenfeldt J, Totsch M, Sheu SY, Robert J, Spiliopoulos A, Frilling A, Schmid KW, Meier CA (2003) Expression of galectin-3 in normal and malignant thyroid tissue by quantitative PCR and immunohistochemistry. Mod Pathol 16:1117–1123
Feinberg AP (2004) The epigenetics of cancer etiology. Semin Cancer Biol 14:427–432
Finley DJ, Arora N, Zhu B, Gallagher L, Fahey TJ III (2004) Molecular profiling distinguishes papillary carcinoma from benign thyroid nodules. J Clin Endocrinol Metab 89:3214–3223
Finley DJ, Zhu B, Barden CB, Fahey TJ III (2004) Discrimination of benign and malignant thyroid nodules by molecular profiling. Ann Surg 240:425–436; discussion 436–427
Galusca B, Dumollard JM, Chambonniere ML, Germain N, Prades JM, Peoc’h M, Estour B (2004) Peroxisome proliferator activated receptor gamma immunohistochemical expression in human papillary thyroid carcinoma tissues. Possible relationship to lymph node metastasis. Anticancer Res 24:1993–1997
Gasbarri A, Marchetti C, Iervasi G, Bottoni A, Nicolini A, Bartolazzi A, Carpi A (2004) From the bench to the bedside. Galectin-3 immunodetection for improving the preoperative diagnosis of the follicular thyroid nodules. Biomed Pharmacother 58:356–359
Gasbarri A, Martegani MP, Del Prete F, Lucante T, Natali PG, Bartolazzi A (1999) Galectin-3 and CD44v6 isoforms in the preoperative evaluation of thyroid nodules. J Clin Oncol 17:3494–3502
Gharib H (2004) Changing trends in thyroid practice: understanding nodular thyroid disease. Endocr Pract 10:31–39
Gharib H, Goellner JR (1993) Fine-needle aspiration biopsy of the thyroid: an appraisal. Ann Intern Med 118:282–289
Hernandez-Blazquez FJ, Habib M, Dumollard JM, Barthelemy C, Benchaib M, de Capoa A, Niveleau A (2000) Evaluation of global DNA hypomethylation in human colon cancer tissues by immunohistochemistry and image analysis. Gut 47:689–693
Huang Y, de la Chapelle A, Pellegata NS (2003) Hypermethylation, but not LOH, is associated with the low expression of MT1G and CRABP1 in papillary thyroid carcinoma. Int J Cancer 104:735–744
Ito Y, Tomoda C, Uruno T, Takamura Y, Miya A, Kobayashi K, Matsuzuka F, Kuma K, Miyauchi A (2004) Papillary microcarcinoma of the thyroid: how should it be treated? World J Surg 28:1115-1121
Ito Y, Uruno T, Nakano K, Takamura Y, Miya A, Kobayashi K, Yokozawa T, Matsuzuka F, Kuma S, Kuma K, Miyauchi A (2003) An observation trial without surgical treatment in patients with papillary microcarcinoma of the thyroid. Thyroid 13:381–387
Jakubiak-Wielganowicz M, Kubiak R, Sygut J, Pomorski L, Kordek R (2003) Usefulness of galectin-3 immunohistochemistry in differential diagnosis between thyroid follicular carcinoma and follicular adenoma. Pol J Pathol 54:111–115
Kini SR, Miller JM, Hamburger JI, Smith-Purslow MJ (1985) Cytopathology of follicular lesions of the thyroid gland. Diagn Cytopathol 1:123–132
LiVolsi VA (1990) Thyroid tumors. In: LiVolsi VA (ed) Surgical pathology of the thyroid. Saunders, Philadelphia, pp 131–212
Martins L, Matsuo SE, Ebina KN, Kulcsar MA, Friguglietti CU, Kimura ET (2002) Galectin-3 messenger ribonucleic acid and protein are expressed in benign thyroid tumors. J Clin Endocrinol Metab 87:4806–4810
Matsuo K, Tang SH, Zeki K, Gutman RA, Fagin JA (1993) Aberrant deoxyribonucleic acid methylation in human thyroid tumors. J Clin Endocrinol Metab 77:991–995
Mehrotra P, Okpokam A, Bouhaidar R, Johnson SJ, Wilson JA, Davies BR, Lennard TW (2004) Galectin-3 does not reliably distinguish benign from malignant thyroid neoplasms. Histopathology 45:493–500
Pichon B, Christophe-Hobertus C, Vassart G, Christophe D (1994) Unmethylated thyroglobulin promoter may be repressed by methylation of flanking DNA sequences. Biochem J 298 Pt 3:537–541
Pineda P, Rojas P, Liberman C, Moyano L, Goecke I (2003) [Detection of malignancy markers in thyroid nodules by reverse transcriptase polymerase chain reaction (RT-PCR)]. Rev Med Chil 131:965–972
Piyathilake CJ, Frost AR, Bell WC, Oelschlager D, Weiss H, Johanning GL, Niveleau A, Heimburger DC, Grizzle WE (2001) Altered global methylation of DNA: an epigenetic difference in susceptibility for lung cancer is associated with its progression. Hum Pathol 32:856–862
Piyathilake CJ, Johanning GL, Frost AR, Whiteside MA, Manne U, Grizzle WE, Heimburger DC, Niveleau A (2000) Immunohistochemical evaluation of global DNA methylation: comparison with in vitro radiolabeled methyl incorporation assay. Biotech Histochem 75:251–258
Saggiorato E, Aversa S, Deandreis D, Arecco F, Mussa A, Puligheddu B, Cappia S, Conticello S, Papotti M, Orlandi F (2004) Galectin-3: presurgical marker of thyroid follicular epithelial cell-derived carcinomas. J Endocrinol Invest 27:311–317
Saggiorato E, Cappia S, De Giuli P, Mussa A, Pancani G, Caraci P, Angeli A, Orlandi F (2001) Galectin-3 as a presurgical immunocytodiagnostic marker of minimally invasive follicular thyroid carcinoma. J Clin Endocrinol Metab 86:5152–5158
Soares J, Pinto AE, Cunha CV, Andre S, Barao I, Sousa JM, Cravo M (1999) Global DNA hypomethylation in breast carcinoma: correlation with prognostic factors and tumor progression. Cancer 85:112–118
Takano T, Miyauchi A, Matsuzuka F, Yoshida H, Kuma K, Amino N (2003) Ubiquitous expression of galectin-3 mRNA in benign and malignant thyroid tumors. Cancer Lett 199:69–73
Teng XD, Wang LJ, Yao HT, Li J, Ding W, Yan LP (2004) Expression of cytokeratin19, galectin-3 and HBME-1 in thyroid lesions and their differential diagnoses. Zhonghua Bing Li Xue Za Zhi 33:212–216
Venkataraman GM, Yatin M, Marcinek R, Ain KB (1999) Restoration of iodide uptake in dedifferentiated thyroid carcinoma: relationship to human Na+/I-symporter gene methylation status. J Clin Endocrinol Metab 84:2449–2457
Volante M, Bozzalla-Cassione F, DePompa R, Saggiorato E, Bartolazzi A, Orlandi F, Papotti M (2004) Galectin-3 and HBME-1 expression in oncocytic cell tumors of the thyroid. Virchows Arch 445:183–188
Volante M, Bozzalla-Cassione F, Orlandi F, Papotti M (2004) Diagnostic role of galectin-3 in follicular thyroid tumors. Virchows Arch 444:309–312
Wang TS, Dubner S, Sznyter LA, Heller KS (2004) Incidence of metastatic well-differentiated thyroid cancer in cervical lymph nodes. Arch Otolaryngol Head Neck Surg 130:110–113
Weber KB, Shroyer KR, Heinz DE, Nawaz S, Said MS, Haugen BR (2004) The use of a combination of galectin-3 and thyroid peroxidase for the diagnosis and prognosis of thyroid cancer. Am J Clin Pathol 122:524–531
Xing M, Tokumaru Y, Wu G, Westra WB, Ladenson PW, Sidransky D (2003) Hypermethylation of the Pendred syndrome gene SLC26A4 is an early event in thyroid tumorigenesis. Cancer Res 63:2312–2315
Xing M, Usadel H, Cohen Y, Tokumaru Y, Guo Z, Westra WB, Tong BC, Tallini G, Udelsman R, Califano JA, Ladenson PW, Sidransky D (2003) Methylation of the thyroid-stimulating hormone receptor gene in epithelial thyroid tumors: a marker of malignancy and a cause of gene silencing. Cancer Res 63:2316–2321
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Galusca, B., Dumollard, J.M., Lassandre, S. et al. Global DNA methylation evaluation: potential complementary marker in differential diagnosis of thyroid neoplasia. Virchows Arch 447, 18–23 (2005). https://doi.org/10.1007/s00428-005-1268-5
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DOI: https://doi.org/10.1007/s00428-005-1268-5