Geographical mapping of a multifocal thyroid tumour using genetic alteration analysis & miRNA profiling

Molecular Cancer - Tập 7 Số 1 - 2008
Sinéad Aherne1, Paul Smyth1, Richard Flavin1, Susan M. Russell2, Karen Denning1, Jing Huan Li1, Simone M Guenther3, John O’Leary1, Orla Sheils1
1Department of Histopathology, Trinity College Dublin, Ireland
2Central Pathology Laboratory, St James’s Hospital, Dublin, Ireland
3Applied Biosystems, Foster City, USA

Tóm tắt

Abstract Background Papillary thyroid carcinoma (PTC) frequently presents as multiple tumour-foci within a single thyroid gland or pluriform, with synchronous tumours comprising different histological variants, raising questions regarding its clonality. Among the genetic aberrations described in PTC, the BRAF V600E mutation and ret/PTC activation occur most commonly. Several studies have investigated the genetic alteration status of multifocal thyroid tumours, with discordant results. To address the question of clonality this study examined disparate geographical and morphological areas from a single PTC (classic PTC, insular and anaplastic foci, and tumour cells adjacent to vascular invasion and lymphocytic infiltrate) for the presence of ret/PTC 1 or BRAF mutations. Moreover, we wanted to investigate the consistency of miRNA signatures within disparate areas of a tumour, and geographical data was further correlated with expression profiles of 330 different miRNAs. Putative miRNA gene targets were predicted for differentially regulated miRNAs and immunohistochemistry was performed on tissue sections in an effort to investigate phenotypic variations in microvascular density (MVD), and cytokeratin and p53 protein expression levels. Results All of the morphological areas proved negative for ret/PTC 1 rearrangement. Two distinct foci with classic morphology harboured the BRAF mutation. All other regions, including the insular and anaplastic areas were negative for the mutation. MiRNA profiles were found to distinguish tumours containing the BRAF mutation from the other tumour types, and to differentiate between the more aggressive insular & anaplastic tumours, and the classic variant. Our data corroborated miRNAs previously discovered in this carcinoma, and additional miRNAs linked to various processes involved in tumour growth and proliferation. Conclusion The initial genetic alteration analysis indicated that pluriform PTC did not necessarily evolve from classic PTC progenitor foci. Analysis of miRNA profiles however provided an interesting variation on the clonality question. While hierarchical clustering analysis of miRNA expression supported the hypothesis that discrete areas did not evolve from clonal expansion of tumour cells, it did not exclude the possibility of independent mutational events suggesting both phenomena might occur simultaneously within a tumour to enhance cancer progression in geographical micro-environments within a tumour.

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Tài liệu tham khảo

Segev DL, Umbricht C, Zeiger MA: Molecular pathogenesis of thyroid cancer. Surg Oncol. 2003, 12: 69-90. 10.1016/S0960-7404(03)00037-9

DeLellis RA: Pathology and genetics of thyroid carcinoma. J Surg Oncol. 2006, 94: 662-669. 10.1002/jso.20700

Xing M: BRAF mutation in thyroid cancer. Endocr Relat Cancer. 2005, 12: 245-262. 10.1677/erc.1.0978

Smyth P, Finn S, Cahill S, O'Regan E, Flavin R, O'Leary JJ, Sheils O: ret/PTC and BRAF act as distinct molecular, time-dependant triggers in a sporadic Irish cohort of papillary thyroid carcinoma. Int J Surg Pathol. 2005, 13: 1-8. 10.1177/106689690501300101

Finn SP, Smyth P, O'Leary J, Sweeney EC, Sheils O: Ret/PTC chimeric transcripts in an Irish cohort of sporadic papillary thyroid carcinoma. J Clin Endocrinol Metab. 2003, 88: 938-941. 10.1210/jc.2002-021239

Thomas GA, Bunnell H, Cook HA, Williams ED, Nerovnya A, Cherstvoy ED, Tronko ND, Bogdanova TI, Chiappetta G, Viglietto G, Pentimalli F, Salvatore G, Fusco A, Santoro M, Vecchio G: High prevalence of RET/PTC rearrangements in Ukrainian and Belarussian post-Chernobyl thyroid papillary carcinomas: a strong correlation between RET/PTC3 and the solid-follicular variant. J Clin Endocrinol Metab. 1999, 84: 4232-4238. 10.1210/jc.84.11.4232

Takano T, Ito Y, Hirokawa M, Yoshida H, Miyauchi A: BRAF V600E mutation in anaplastic thyroid carcinomas and their accompanying differentiated carcinomas. Br J Cancer. 2007, 96: 1549-1553. 10.1038/sj.bjc.6603764

Giannini R, Ugolini C, Lupi C, Proietti A, Elisei R, Salvatore G, Berti P, Materazzi G, Miccoli P, Santoro M, Basolo F: 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: 3511-3516. 10.1210/jc.2007-0594

Wang HM, Huang YW, Huang JS, Wang CH, Kok VC, Hung CM, Chen HM, Tzen CY: Anaplastic carcinoma of the thyroid arising more often from follicular carcinoma than papillary carcinoma. Ann Surg Oncol. 2007, 14: 3011-3018. 10.1245/s10434-007-9418-4

McCarthy RP, Wang M, Jones TD, Strate RW, Cheng L: Molecular evidence for the same clonal origin of multifocal papillary thyroid carcinomas. Clin Cancer Res. 2006, 12: 2414-2418. 10.1158/1078-0432.CCR-05-2818

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. 10.1002/cncr.22218

Quiros RM, Ding HG, Gattuso P, Prinz RA, Xu X: Evidence that one subset of anaplastic thyroid carcinomas are derived from papillary carcinomas due to BRAF and p53 mutations. Cancer. 2005, 103: 2261-2268. 10.1002/cncr.21073

Shattuck TM, Westra WH, Ladenson PW, Arnold A: Independent clonal origins of distinct tumor foci in multifocal papillary thyroid carcinoma. N Engl J Med. 2005, 352: 2406-2412. 10.1056/NEJMoa044190

Begum S, Rosenbaum E, Henrique R, Cohen Y, Sidransky D, Westra WH: BRAF mutations in anaplastic thyroid carcinoma: implications for tumor origin, diagnosis and treatment. Mod Pathol. 2004, 17: 1359-1363. 10.1038/modpathol.3800198

Sugg SL, Ezzat S, Rosen IB, Freeman JL, Asa SL: Distinct multiple RET/PTC gene rearrangements in multifocal papillary thyroid neoplasia. J Clin Endocrinol Metab. 1998, 83: 4116-4122. 10.1210/jc.83.11.4116

Carthew RW: Gene regulation by microRNAs. Curr Opin Genet Dev. 2006, 16: 203-208. 10.1016/j.gde.2006.02.012

Griffiths-Jones S, Grocock RJ, van Dongen S, Bateman A, Enright AJ: miRBase: microRNA sequences, targets and gene nomenclature. Nucleic Acids Res. 2006, 34: D140-144. 10.1093/nar/gkj112

Cummins JM, Velculescu VE: Implications of micro-RNA profiling for cancer diagnosis. Oncogene. 2006, 25: 6220-6227. 10.1038/sj.onc.1209914

He H, Jazdzewski K, Li W, Liyanarachchi S, Nagy R, Volinia S, Calin GA, Liu CG, Franssila K, Suster S, Kloos RT, Croce CM, de la Chapelle A: The role of microRNA genes in papillary thyroid carcinoma. Proc Natl Acad Sci USA. 2005, 102: 19075-19080. 10.1073/pnas.0509603102

Pallante P, Visone R, Ferracin M, Ferraro A, Berlingieri MT, Troncone G, Chiappetta G, Liu CG, Santoro M, Negrini M, Croce CM, Fusco A: MicroRNA deregulation in human thyroid papillary carcinomas. Endocr Relat Cancer. 2006, 13: 497-508. 10.1677/erc.1.01209

Nikiforova MN, Tseng GC, Steward D, Diorio D, Nikiforov YE: MicroRNA Expression Profiling of Thyroid Tumors: Biological Significance and Diagnostic Utility. J Clin Endocrinol Metab. 2008.

Mazzaferri EL, Jhiang SM: Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer. Am J Med. 1994, 97: 418-428. 10.1016/0002-9343(94)90321-2

Chen C, Ridzon DA, Broomer AJ, Zhou Z, Lee DH, Nguyen JT, Barbisin M, Xu NL, Mahuvakar VR, Andersen MR, Lao KQ, Livak KJ, Guegler KJ: Real-time quantification of microRNAs by stem-loop RT-PCR. Nucleic Acids Res. 2005, 33: e179- 10.1093/nar/gni178

Rosai JCM, Delellis RA: Tumors of the Thyroid Gland Atlas of Tumor Pathology. 1992, Washington, DC: Armed Forces Institute of Pathology.

Lao K, Xu NL, Yeung V, Chen C, Livak KJ, Straus NA: Multiplexing RT-PCR for the detection of multiple miRNA species in small samples. Biochem Biophys Res Commun. 2006, 343: 85-89. 10.1016/j.bbrc.2006.02.106

Megraw M, Sethupathy P, Corda B, Hatzigeorgiou AG: miRGen: a database for the study of animal microRNA genomic organization and function. Nucleic Acids Res. 2007, 35: D149-155. 10.1093/nar/gkl904

Nisolle M, Gillerot S, Casanas-Roux F, Squifflet J, Berliere M, Donnez J: Immunohistochemical study of the proliferation index, oestrogen receptors and progesterone receptors A and B in leiomyomata and normal myometrium during the menstrual cycle and under gonadotrophin-releasing hormone agonist therapy. Hum Reprod. 1999, 14: 2844-2850. 10.1093/humrep/14.11.2844

Livak KJ, Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001, 25: 402-408. 10.1006/meth.2001.1262

Dalmay T, Edwards DR: MicroRNAs and the hallmarks of cancer. Oncogene. 2006, 25: 6170-6175. 10.1038/sj.onc.1209911

Volinia S, Calin GA, Liu CG, Ambs S, Cimmino A, Petrocca F, Visone R, Iorio M, Roldo C, Ferracin M, Prueitt RL, Yanaihara N, Lanza G, Scarpa A, Vecchione A, Negrini M, Harris CC, Croce CM: A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci USA. 2006, 103: 2257-2261. 10.1073/pnas.0510565103

Cahill S, Smyth P, Finn SP, Denning K, Flavin R, O'Regan EM, Li J, Potratz A, Guenther SM, Henfrey R, O'Leary JJ, Sheils O: Effect of ret/PTC 1 rearrangement on transcription and post-transcriptional regulation in a papillary thyroid carcinoma model. Mol Cancer. 2006, 5: 70- 10.1186/1476-4598-5-70

Cahill S, Smyth P, Denning K, Flavin R, Li J, Potratz A, Guenther SM, Henfrey R, O'Leary JJ, Sheils O: Effect of BRAFV600E mutation on transcription and post-transcriptional regulation in a papillary thyroid carcinoma model. Mol Cancer. 2007, 6: 21- 10.1186/1476-4598-6-21

He L, He X, Lim LP, de Stanchina E, Xuan Z, Liang Y, Xue W, Zender L, Magnus J, Ridzon D, Jackson AL, Linsley PS, Chen C, Lowe SW, Cleary MA, Hannon GJ: A microRNA component of the p53 tumour suppressor network. Nature. 2007, 447: 1130-1134. 10.1038/nature05939

Chuang JC, Jones PA: Epigenetics and microRNAs. Pediatr Res. 2007, 61: 24R-29R. 10.1203/pdr.0b013e3180457684

Cho RJ, Campbell MJ: Transcription, genomes, function. Trends Genet. 2000, 16: 409-415. 10.1016/S0168-9525(00)02065-5

Turner HE, Harris AL, Melmed S, Wass JA: Angiogenesis in endocrine tumors. Endocr Rev. 2003, 24: 600-632. 10.1210/er.2002-0008

Are C, Shaha AR: Anaplastic thyroid carcinoma: biology, pathogenesis, prognostic factors, and treatment approaches. Ann Surg Oncol. 2006, 13: 453-464. 10.1245/ASO.2006.05.042

Garcia-Jimenez C, Santisteban P: TSH signalling and cancer. Arq Bras Endocrinol Metabol. 2007, 51: 654-671.

Kikuchi A: Tumor formation by genetic mutations in the components of the Wnt signaling pathway. Cancer Sci. 2003, 94: 225-229. 10.1111/j.1349-7006.2003.tb01424.x

Abbosh PH, Nephew KP: Multiple signaling pathways converge on beta-catenin in thyroid cancer. Thyroid. 2005, 15: 551-561. 10.1089/thy.2005.15.551

Benjamin JM, Nelson WJ: Bench to bedside and back again: molecular mechanisms of alpha-catenin function and roles in tumorigenesis. Semin Cancer Biol. 2008, 18: 53-64. 10.1016/j.semcancer.2007.08.003

Smyth P, Sheils O, Finn S, Martin C, O'Leary J, Sweeney EC: Real-time quantitative analysis of E-cadherin expression in ret/PTC-1-activated thyroid neoplasms. Int J Surg Pathol. 2001, 9: 265-272. 10.1177/106689690100900402

Hassan I, Wunderlich A, Slater E, Hoffmann S, Celik I, Zielke A: Antisense p53 decreases production of VEGF in follicular thyroid cancer cells. Endocrine. 2006, 29: 409-412. 10.1385/ENDO:29:3:409

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Molecular Cancer

Tập 7 Số 1

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