Thyroid follicular adenomas and carcinomas: molecular profiling provides evidence for a continuous evolution

Geneviève Dom, Sandra Frank, Sebastien Floor, Pashalina Kehagias, Frederick Libert, Catherine Hoang, Guy Andry, Alex Spinette, Ligia Craciun, Nicolas de Saint Aubin, Christophe Tresallet, Frederique Tissier, Frederique Savagner, Samira Majjaj, Ilse Gutierrez-Roelens, Etienne Marbaix, Jacques E Dumont, Carine Maenhaut, Geneviève Dom, Sandra Frank, Sebastien Floor, Pashalina Kehagias, Frederick Libert, Catherine Hoang, Guy Andry, Alex Spinette, Ligia Craciun, Nicolas de Saint Aubin, Christophe Tresallet, Frederique Tissier, Frederique Savagner, Samira Majjaj, Ilse Gutierrez-Roelens, Etienne Marbaix, Jacques E Dumont, Carine Maenhaut

Abstract

Non-autonomous thyroid nodules are common in the general population with a proportion found to be cancerous. A current challenge in the field is to be able to distinguish benign adenoma (FA) from preoperatively malignant thyroid follicular carcinoma (FTC), which are very similar both histologically and genetically. One controversial issue, which is currently not understood, is whether both tumor types represent different molecular entities or rather a biological continuum. To gain a better insight into FA and FTC tumorigenesis, we defined their molecular profiles by mRNA and miRNA microarray. Expression data were analyzed, validated by qRT-PCR and compared with previously published data sets. The majority of deregulated mRNAs were common between FA and FTC and were downregulated, however FTC showed additional deregulated mRNA. Both types of tumors share deregulated pathways, molecular functions and biological processes. The additional deregulations in FTC include the lipid transport process that may be involved in tumor progression. The strongest candidate genes which may be able to discriminate follicular adenomas and carcinomas, CRABP1, FABP4 and HMGA2, were validated in independent samples by qRT-PCR and immunohistochemistry. However, they were not able to adequately classify FA or FTC, supporting the notion of continuous evolving tumors, whereby FA and FTC appear to show quantitative rather than qualitative changes. Conversely, miRNA expression profiles showed few dysregulations in FTC, and even fewer in FA, suggesting that miRNA play a minor, if any, role in tumor progression.

Keywords: malignant progression mRNA; miRNA; thyroid follicular adenoma; thyroid follicular carcinoma.

Conflict of interest statement

CONFLICTS OF INTEREST The authors have no conflicts of interest to declare.

Figures

Figure 1
Figure 1
(A) Multidimensional Scaling (MDS) of the mRNA expression values from 20 FA and 8 FTC: all the probes present on the array were considered (FTC are encircled). (B) FTC and FA deregulated mRNA (fold change ≥|2| q-value ≤ 5%). Venn diagram of the significantly regulated mRNA in 20 FA and 8 FTC hybridized on Heebo slides (SAM 1 class analysis, R bioconductor).
Figure 2. Confirmation of the microarray data…
Figure 2. Confirmation of the microarray data by qRT-PCR
Validation of the modulation of 9 genes by qRT-PCR. The microarray expressions are also represented. Log2 ratios represent the expression ratios of the genes in the tumors versus normal adjacent tissues. Error bars represent the standard deviation.
Figure 3. Expression ratios (tumor/normal) (log 2…
Figure 3. Expression ratios (tumor/normal) (log2) of CRABP1, FABP4, and HMGA2 in various data sets of FA and FTC
(A) our HEEBO microarray results. (B) qRT-PCR on independent samples. (C) Borup's Affymetrix microarray data [17] (nFA = 22, nFTC = 18). (D) our Affymetrix microarray data (n = 9). (T: tumor; N: normal).
Figure 4
Figure 4
Immunolabelling of follicular adenomas (n = 16) (A) and follicular carcinoma (n = 17) (B) and normal adjacent tissues for CRABP1, FABP4 and HMGA2. Magnification 40×.
Figure 5. Multidimensional scaling (MDS) of the…
Figure 5. Multidimensional scaling (MDS) of the miRNA expression data from 10 FA and 9 FTC
All the probes present on the array were considered (FTC are encircled).
Figure 6
Figure 6
(A) mRNA expression of FABP4 in FA and FTC samples, and MDS with all the microarray expression data in FA and FTC samples: both one of the most performant markers and the expression data at global level highlight the idea of a continuum. (B) mRNA expression of PKP4 in ATC and PTC samples, and MDS with all the microarray expression data in ATC and PTC samples (37): in ATC and PTC, molecular markers split up the 2 samples groups.

References

    1. Sobrinho-Simões M, Eloy C, Magalhães J, Lobo C, Amaro T. Follicular thyroid carcinoma. Mod Pathol. 2011;24:S10–18.
    1. McHenry CR, Phitayakorn R. Follicular adenoma and carcinoma of the thyroid gland. Oncologist. 2011;16:585–93.
    1. Krause K, Prawitt S, Eszlinger M, Ihling C, Sinz A, Schierle K, Gimm O, Dralle H, Steinert F, Sheu SY, Schmid KW, Fuhrer D. Dissecting molecular events in thyroid neoplasia provides evidence for distinct evolution of follicular thyroid adenoma and carcinoma. Am J Pathol. 2011;179:3066–74.
    1. Karger S, Krause K, Engelhardt C, Weidinger C, Gimm O, Dralle H, Sheu-Grabellus SY, Schmid KW, Fuhrer D. Distinct pattern of oxidative DNA damage and DNA repair in follicular thyroid tumours. J Mol Endocrinol. 2012;48:193–202.
    1. Gupta N, Dasyam AK, Carty SE, Nikiforova MN, Ohori NP, Armstrong M, Yip L, LeBeau SO, McCoy KL, Coyne C, Stang MT, Johnson J, Ferris RL, et al. RAS mutations in thyroid FNA specimens are highly predictive of predominantly low-risk follicular-pattern cancers. J Clin Endocrinol Metab. 2013;98:E914–22.
    1. Nikiforov YE, Ohori NP, Hodak SP, Carty SE, LeBeau SO, Ferris RL, Yip L, Seethala RR, Tublin ME, Stang MT, Coyne C, Johnson JT, Stewart AF, Nikiforova MN. 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;96:3390–97.
    1. Le Mercier M, D'Haene N, De Nève N, Blanchard O, Degand C, Rorive S, Salmon I. Next-generation sequencing improves the diagnosis of thyroid FNA specimens with indeterminate cytology. Histopathology. 2015;66:215–24.
    1. Hsiao SJ, Nikiforov YE. Molecular approaches to thyroid cancer diagnosis. Endocr Relat Cancer. 2014;21:T301–13.
    1. Nikiforova MN, Wald AI, Roy S, Durso MB, Nikiforov YE. Targeted next-generation sequencing panel (ThyroSeq) for detection of mutations in thyroid cancer. J Clin Endocrinol Metab. 2013;98:E1852–60.
    1. Pagan M, Kloos RT, Lin CF, Travers KJ, Matsuzaki H, Tom EY, Kim SY, Wong MG, Stewart AC, Huang J, Walsh PS, Monroe RJ, Kennedy GC. The diagnostic application of RNA sequencing in patients with thyroid cancer: an analysis of 851 variants and 133 fusions in 524 genes. BMC Bioinformatics. 2016;17:6.
    1. Nishino M. Molecular cytopathology for thyroid nodules: A review of methodology and test performance. Cancer Cytopathol. 2016(124):14–27.
    1. Alexander EK, Kennedy GC, Baloch ZW, Cibas ES, Chudova D, Diggans J, Friedman L, Kloos RT, LiVolsi VA, Mandel SJ, Raab SS, Rosai J, Steward DL, et al. Preoperative diagnosis of benign thyroid nodules with indeterminate cytology. N Engl J Med. 2012;367:705–15.
    1. Labourier E, Shifrin A, Busseniers AE, Lupo MA, Manganelli ML, Andruss B, Wylie D, Beaudenon-Huibregtse S. Molecular testing for miRNA, mRNA, and DNA on fine-needle aspiration improves the preoperative diagnosis of thyroid nodules with indeterminate cytology. J Clin Endocrinol Metab. 2015;100:2743–50.
    1. Benjamin H, Schnitzer-Perlman T, Shtabsky A, VandenBussche CJ, Ali SZ, Kolar Z, Pagni F, Bar D, Meiri E, Rosetta Genomics Group Analytical validity of a microRNA-based assay for diagnosing indeterminate thyroid FNA smears from routinely prepared cytology slides. Cancer Cytopathol. 2016;124:711–21.
    1. Nikiforov YE, Carty SE, Chiosea SI, Coyne C, Duvvuri U, Ferris RL, Gooding WE, Hodak SP, LeBeau SO, Ohori NP, Seethala RR, Tublin ME, Yip L, Nikiforova MN. Highly accurate diagnosis of cancer in thyroid nodules with follicular neoplasm/suspicious for a follicular neoplasm cytology by ThyroSeq v2 next-generation sequencing assay. Cancer. 2014;120:3627–34.
    1. Dennis G, Sherman BT, Hosack DA, Yang J, Gao W, Lane HC, Lempicki RA, Hosack DA, Yang J, Gao W, Lane HC, Lempicki RA. DAVID: Database for Annotation, Visualization, and Integrated Discovery. Genome Biol. 2003;4:3.
    1. Borup R, Rossing M, Henao R, Yamamoto Y, Krogdahl A, Godballe C, Winther O, Kiss K, Christensen L, Høgdall E, Bennedbaek F, Nielsen FC. Molecular signatures of thyroid follicular neoplasia. Endocr Relat Cancer. 2010;17:691–708.
    1. Finley DJ, Zhu B, Barden CB, Fahey TJ. Discrimination of benign and malignant thyroid nodules by molecular profiling. Ann Surg. 2004;240:425–36. discussion 436-7 .
    1. Weber F, Shen L, Aldred MA, Morrison CD, Frilling A, Saji M, Schuppert F, Broelsch CE, Ringel MD, Eng C. Genetic classification of benign and malignant thyroid follicular neoplasia based on a three-gene combination. J Clin Endocrinol Metab. 2005;90:2512–21.
    1. Giordano TJ, Au AY, Kuick R, Thomas DG, Rhodes DR, Wilhelm KG, Jr, Vinco M, Misek DE, Sanders D, Zhu Z, Ciampi R, Hanash S, Chinnaiyan A, et al. Delineation, functional validation, and bioinformatic evaluation of gene expression in thyroid follicular carcinomas with the PAX8-PPARG translocation. Clin Cancer Res. 2006;12:1983–93.
    1. Fontaine JF, Mirebeau-Prunier D, Raharijaona M, Franc B, Triau S, Rodien P, Goëau-Brissonniére O, Karayan-Tapon L, Mello M, Houlgatte R, Malthiery Y, Savagner F. Increasing the number of thyroid lesions classes in microarray analysis improves the relevance of diagnostic markers. PLoS One. 2009;4:e7632.
    1. Rossing M, Borup R, Henao R, Winther O, Vikesaa J, Niazi O, Godballe C, Krogdahl A, Glud M, Hjort-Sørensen C, Kiss K, Bennedbæk FN, Nielsen FC. Down-regulation of microRNAs controlling tumourigenic factors in follicular thyroid carcinoma. J Mol Endocrinol. 2012;48:11–23.
    1. Stokowy T, Wojtaś B, Krajewska J, Stobiecka E, Dralle H, Musholt T, Hauptmann S, Lange D, Hegedüs L, Jarząb B, Krohn K, Paschke R, Eszlinger M. A two miRNA classifier differentiates follicular thyroid carcinomas from follicular thyroid adenomas. Mol Cell Endocrinol. 2015;399:43–49.
    1. Reddi HV, Madde P, Milosevic D, Hackbarth JS, Algeciras-Schimnich A, McIver B, Grebe SK, Eberhardt NL. 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;2:46–55.
    1. Weber F, Teresi RE, Broelsch CE, Frilling A, Eng C. A limited set of human MicroRNA is deregulated in follicular thyroid carcinoma. J Clin Endocrinol Metab. 2006;91:3584–91.
    1. Mancikova V, Castelblanco E, Pineiro-Yanez E, Perales-Paton J, de Cubas AA, Inglada-Perez L, Matias-Guiu X, Capel I, Bella M, Lerma E, Riesco-Eizaguirre G, Santisteban P, Maravall F, et al. MicroRNA deep-sequencing reveals master regulators of follicular and papillary thyroid tumors. Mod Pathol. 2015;28:748–57.
    1. Stokowy T, Wojtaś B, Fujarewicz K, Jarząb B, Eszlinger M, Paschke R. miRNAs with the potential to distinguish follicular thyroid carcinomas from benign follicular thyroid tumors: results of a meta-analysis. Horm Metab Res. 2014;46:171–80.
    1. Stokowy T, Eszlinger M, Świerniak M, Fujarewicz K, Jarząb B, Paschke R, Krohn K. Analysis options for high-throughput sequencing in miRNA expression profiling. BMC Res Notes. 2014;7:144.
    1. Franc B, de la Salmonière P, Lange F, Hoang C, Louvel A, de Roquancourt A, Vildé F, Hejblum G, Chevret S, Chastang C. Interobserver and intraobserver reproducibility in the histopathology of follicular thyroid carcinoma. Hum Pathol. 2003;34:1092–100.
    1. Mazzaferri EL, Jhiang SM. Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer. Am J Med. 1994;97:418–28.
    1. Letsas KP, Frangou-Lazaridis M, Skyrlas A, Tsatsoulis A, Malamou-Mitsi V. Transcription factor-mediated proliferation and apoptosis in benign and malignant thyroid lesions. Pathol Int. 2005;55:694–702.
    1. Katoh R, Bray CE, Suzuki K, Komiyama A, Hemmi A, Kawaoi A, Oyama T, Sugai T, Sasou S. Growth activity in hyperplastic and neoplastic human thyroid determined by an immunohistochemical staining procedure using monoclonal antibody MIB-1. Hum Pathol. 1995;26:139–46.
    1. Jang MH, Jung KC, Min HS. The Diagnostic Usefulness of HMGA2, Survivin, CEACAM6, and SFN/14-3-3 δ in Follicular Thyroid Carcinoma. J Pathol Transl Med. 2015;49:112–17.
    1. Hirokawa M, Carney JA, Goellner JR, DeLellis RA, Heffess CS, Katoh R, Tsujimoto M, Kakudo K. Observer variation of encapsulated follicular lesions of the thyroid gland. Am J Surg Pathol. 2002;26:1508–14.
    1. Pfeifer A, Wojtas B, Oczko-Wojciechowska M, Kukulska A, Czarniecka A, Eszlinger M, Musholt T, Stokowy T, Swierniak M, Stobiecka E, Rusinek D, Tyszkiewicz T, Kowal M, et al. Molecular differential diagnosis of follicular thyroid carcinoma and adenoma based on gene expression profiling by using formalin-fixed paraffin-embedded tissues. BMC Med Genomics. 2013;6:38.
    1. Fryknäs M, Wickenberg-Bolin U, Göransson H, Gustafsson MG, Foukakis T, Lee JJ, Landegren U, Höög A, Larsson C, Grimelius L, Wallin G, Pettersson U, Isaksson A. Molecular markers for discrimination of benign and malignant follicular thyroid tumors. Tumour Biol. 2006;27:211–20.
    1. Hébrant A, Dom G, Dewaele M, Andry G, Trésallet C, Leteurtre E, Dumont JE, Maenhaut C. mRNA expression in papillary and anaplastic thyroid carcinoma: molecular anatomy of a killing switch. PLoS One. 2012;7:e37807.
    1. Schmid KW, Farid NR. How to define follicular thyroid carcinoma? Virchows Arch. 2006;448:385–93.
    1. Derwahl M, Studer H. Hyperplasia versus adenoma in endocrine tissues: are they different? Trends Endocrinol Metab. 2002;13:23–28.
    1. Hébrant A, Floor S, Saiselet M, Antoniou A, Desbuleux A, Snyers B, La C, de Saint Aubain N, Leteurtre E, Andry G, Maenhaut C. miRNA expression in anaplastic thyroid carcinomas. PLoS One. 2014;9:e103871.
    1. Belge G, Meyer A, Klemke M, Burchardt K, Stern C, Wosniok W, Loeschke S, Bullerdiek J. Upregulation of HMGA2 in thyroid carcinomas: a novel molecular marker to distinguish between benign and malignant follicular neoplasias. Genes Chromosomes Cancer. 2008;47:56–63.
    1. Lappinga PJ, Kip NS, Jin L, Lloyd RV, Henry MR, Zhang J, Nassar A. HMGA2 gene expression analysis performed on cytologic smears to distinguish benign from malignant thyroid nodules. Cancer Cytopathol. 2010;118:287–97.
    1. Prasad NB, Kowalski J, Tsai HL, Talbot K, Somervell H, Kouniavsky G, Wang Y, Dackiw AP, Westra WH, Clark DP, Libutti SK, Umbricht CB, Zeiger MA. Three-gene molecular diagnostic model for thyroid cancer. Thyroid. 2012;22:275–84.
    1. Jin L, Lloyd RV, Nassar A, Lappinga PJ, Sebo TJ, Swartz K, Seys AR, Erickson-Johnson MR, Roth CW, Evers BR, Oliveira AM, Zhang J. HMGA2 expression analysis in cytological and paraffin-embedded tissue specimens of thyroid tumors by relative quantitative RT-PCR. Diagn Mol Pathol. 2011;20:71–80.
    1. Rogalla P, Drechsler K, Kazmierczak B, Rippe V, Bonk U, Bullerdiek J. Expression of HMGI-C, a member of the high mobility group protein family, in a subset of breast cancers: relationship to histologic grade. Mol Carcinog. 1997;19:153–56.
    1. Mahajan A, Liu Z, Gellert L, Zou X, Yang G, Lee P, Yang X, Wei JJ. HMGA2: a biomarker significantly overexpressed in high-grade ovarian serous carcinoma. Mod Pathol. 2010;23:673–81.
    1. Pallante P, Sepe R, Puca F, Fusco A. High mobility group a proteins as tumor markers. Front Med (Lausanne) 2015;2:15.
    1. Meyer B, Loeschke S, Schultze A, Weigel T, Sandkamp M, Goldmann T, Vollmer E, Bullerdiek J. HMGA2 overexpression in non-small cell lung cancer. Mol Carcinog. 2007;46:503–11.
    1. Tomás G, Tarabichi M, Gacquer D, Hébrant A, Dom G, Dumont JE, Keutgen X, Fahey TJ, 3rd, Maenhaut C, Detours V. A general method to derive robust organ-specific gene expression-based differentiation indices: application to thyroid cancer diagnostic. Oncogene. 2012;31:4490–98.
    1. Finn SP, Smyth P, Cahill S, Streck C, O'Regan EM, Flavin R, Sherlock J, Howells D, Henfrey R, Cullen M, Toner M, Timon C, O'Leary JJ, Sheils OM. Expression microarray analysis of papillary thyroid carcinoma and benign thyroid tissue: emphasis on the follicular variant and potential markers of malignancy. Virchows Arch. 2007;450:249–60.
    1. Furuhashi M, Saitoh S, Shimamoto K, Miura T. Fatty Acid-Binding Protein 4 (FABP4): Pathophysiological Insights and Potent Clinical Biomarker of Metabolic and Cardiovascular Diseases. Clin Med Insights Cardiol. 2015;8:23–33.
    1. Dobson ME, Diallo-Krou E, Grachtchouk V, Yu J, Colby LA, Wilkinson JE, Giordano TJ, Koenig RJ. Pioglitazone induces a proadipogenic antitumor response in mice with PAX8-PPARgamma fusion protein thyroid carcinoma. Endocrinology. 2011;152:4455–65.
    1. Gorbenko O, Panayotou G, Zhyvoloup A, Volkova D, Gout I, Filonenko V. Identification of novel PTEN-binding partners: PTEN interaction with fatty acid binding protein FABP4. Mol Cell Biochem. 2010;337:299–305.
    1. Ban Y, Yamamoto G, Takada M, Hayashi S, Ban Y, Shimizu K, Akasu H, Igarashi T, Bando Y, Tachikawa T, Hirano T. Proteomic profiling of thyroid papillary carcinoma. J Thyroid Res. 2012;2012:815079.
    1. Schulze A, Harris AL. How cancer metabolism is tuned for proliferation and vulnerable to disruption. Nature. 2012;491:364–73.
    1. Currie E, Schulze A, Zechner R, Walther TC, Farese RV., Jr Cellular fatty acid metabolism and cancer. Cell Metab. 2013;18:153–61.
    1. Guo S, Qiu L, Wang Y, Qin X, Liu H, He M, Zhang Y, Li Z, Chen X. Tissue imaging and serum lipidomic profiling for screening potential biomarkers of thyroid tumors by matrix-assisted laser desorption/ionization-Fourier transform ion cyclotron resonance mass spectrometry. Anal Bioanal Chem. 2014;406:4357–70.
    1. Wojakowska A, Chekan M, Marczak Ł, Polanski K, Lange D, Pietrowska M, Widlak P. Detection of metabolites discriminating subtypes of thyroid cancer: molecular profiling of FFPE samples using the GC/MS approach. Mol Cell Endocrinol. 2015;417:149–57.
    1. von Roemeling CA, Marlow LA, Pinkerton AB, Crist A, Miller J, Tun HW, Smallridge RC, Copland JA. Aberrant lipid metabolism in anaplastic thyroid carcinoma reveals stearoyl CoA desaturase 1 as a novel therapeutic target. J Clin Endocrinol Metab. 2015;100:E697–709.
    1. Riesco-Eizaguirre G, Santisteban P. New insights in thyroid follicular cell biology and its impact in thyroid cancer therapy. Endocr Relat Cancer. 2007;14:957–77.
    1. Robbins HL, Hague A. The PI3K/Akt Pathway in Tumors of Endocrine Tissues. Front Endocrinol (Lausanne) 2016;6:188.
    1. Matsuda S, Nakanishi A, Wada Y, Kitagishi Y. Roles of PI3K/AKT/PTEN Pathway as a Target for Pharmaceutical Therapy. Open Med Chem J. 2013;7:23–29.
    1. Saiselet M, Pita JM, Augenlicht A, Dom G, Tarabichi M, Fimereli D, Dumont JE, Detours V, Maenhaut C. miRNA expression and function in thyroid carcinomas: a comparative and critical analysis and a model for other cancers. Oncotarget. 2016;7:52475–92.
    1. Floor SL, Hebrant A, Pita JM, Saiselet M, Trésallet C, Libert F, Andry G, Dumont JE, van Staveren WC, Maenhaut C. MiRNA expression may account for chronic but not for acute regulation of mRNA expression in human thyroid tumor models. PLoS One. 2014;9:e111581.
    1. Dal Maso L, Bosetti C, La Vecchia C, Franceschi S. Risk factors for thyroid cancer: an epidemiological review focused on nutritional factors. Cancer Causes Control. 2009;20:75–86.
    1. Yoon JH, Kim EK, Youk JH, Moon HJ, Kwak JY. Better understanding in the differentiation of thyroid follicular adenoma, follicular carcinoma, and follicular variant of papillary carcinoma: a retrospective study. Int J Endocrinol. 2014;2014:321595.
    1. Ghossein R. Problems and controversies in the histopathology of thyroid carcinomas of follicular cell origin. Arch Pathol Lab Med. 2009;133:683–91.
    1. Cancer T, Atlas G, Cancer Genome Atlas Research Network Integrated genomic characterization of papillary thyroid carcinoma. Cell. 2014;159:676–90.
    1. Mehrzad R, Nishino M, Connolly J, Wang H, Mowschenson P, Hasselgren PO. The relationship between the follicular variant of papillary thyroid cancer and follicular adenomas. Surgery. 2016;159:1396–406.
    1. Nikiforov YE, Seethala RR, Tallini G, Baloch ZW, Basolo F, Thompson LD, Barletta JA, Wenig BM, Al Ghuzlan A, Kakudo K, Giordano TJ, Alves VA, Khanafshar E, et al. Nomenclature Revision for Encapsulated Follicular Variant of Papillary Thyroid Carcinoma: A Paradigm Shift to Reduce Overtreatment of Indolent Tumors. JAMA Oncol. 2016;2:1023–29.
    1. Stratton MR, Campbell PJ, Futreal PA. The cancer genome. Nature. 2009;458:719–24.
    1. Xing M. Molecular pathogenesis and mechanisms of thyroid cancer. Nat Rev Cancer. 2013;13:184–99.
    1. Kondo T, Ezzat S, Asa SL. Pathogenetic mechanisms in thyroid follicular-cell neoplasia. Nat Rev Cancer. 2006;6:292–306.
    1. Saiselet M, Floor S, Tarabichi M, Dom G, Hébrant A, van Staveren WC, Maenhaut C. Thyroid cancer cell lines: an overview. Front Endocrinol (Lausanne) 2012;3:133.
    1. Hébrant A, Van Sande J, Roger PP, Patey M, Klein M, Bournaud C, Savagner F, Leclère J, Dumont JE, van Staveren WC, Maenhaut C. Thyroid gene expression in familial nonautoimmune hyperthyroidism shows common characteristics with hyperfunctioning autonomous adenomas. J Clin Endocrinol Metab. 2009;94:2602–09.
    1. Delys L, Detours V, Franc B, Thomas G, Bogdanova T, Tronko M, Libert F, Dumont JE, Maenhaut C. Gene expression and the biological phenotype of papillary thyroid carcinomas. Oncogene. 2007;26:7894–903.
    1. Simon R, Lam A, Li MC, Ngan M, Menenzes S, Zhao Y. Analysis of gene expression data using BRB-ArrayTools. Cancer Inform. 2007;3:11–17.
    1. Tusher VG, Tibshirani R, Chu G. Significance analysis of microarrays applied to the ionizing radiation response. Proc Natl Acad Sci USA. 2001;98:5116–21.
    1. Gentleman RC, Carey VJ, Bates DM, Bolstad B, Dettling M, Dudoit S, Ellis B, Gautier L, Ge Y, Gentry J, Hornik K, Hothorn T, Huber W, et al. Bioconductor: open software development for computational biology and bioinformatics. Genome Biol. 2004;5:R80.
    1. Reich M, Liefeld T, Gould J, Lerner J, Tamayo P, Mesirov JP, Chapman SJ, Khor CC, Davies WH, Hedley EL, Segal S, Moore CE, Knox K, et al. GenePattern 2.0. Nat Genet. 2006;38:500–01.
    1. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES, Mesirov JP. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA. 2005;102:15545–50.
    1. Mi H, Poudel S, Muruganujan A, Casagrande JT, Thomas PD. PANTHER version 10: expanded protein families and functions, and analysis tools. Nucleic Acids Res. 2016;44:D336–42.

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