Identification of Genes Associated with Papillary Thyroid Carcinoma (PTC) for Diagnosis by Integrated Analysis

Abstract

Papillary thyroid carcinoma (PTC) is the most common type of thyroid carcinoma, and our understanding of its pathogenesis is incomplete. To elucidate the mechanisms underlying such progression and identify novel diagnostic markers, we aimed to discover the underlying gene associated with PTC. Integrated analysis of microarray datasets was performed to identify differentially expressed genes (DEGs) between PTCs and normal tissues. GO enrichment analysis and KEGG pathway enrichment analysis were then performed to uncover the functions of DEGs. Furthermore, the protein-protein interaction (PPI) network of DEGs was constructed. Five GEO datasets were obtained. Totally, 154 DEGs across the studies were identified, including 26 upregulated and 128 downregulated DEGs. In the PPI network, MLLT1, DLG2, and EFEMP1 were the hub proteins, in which DLG2 and EFEMP1 were involved in tumor progression. Among the top 10 up- and downregulated genes, the dysregulation genes of TPO, CDH16, and MPPED2 may be closely related to the tumorigenesis of PTC. By integrated analysis of multiple gene expression profiles, we propose that the dysregulation genes of TPO and MPPED2 will be the promising diagnostic markers for PTCs.

Key words

papillary thyroid carcinoma - integrated analysis - differentially expressed genes

^*  These authors contributed equally to the work

• References

• 1 Chen AY, Jemal A, Ward EM. Increasing incidence of differentiated thyroid cancer in the United States, 1988–2005. Cancer 2009; 115: 3801-3807
• 2 Fan YL, Li XQ. Expression of leptin and its receptor in thyroid carcinoma: distinctive prognostic significance in different subtypes. Clin Endocrinol 2015; 83: 261-267
• 3 Hay ID, Thompson GB, Grant CS, Bergstralh EJ, Dvorak CE, Gorman CA, Maurer MS, McIver B, Mullan BP, Oberg AL, Powell CC, van Heerden JA, Goellner JR. Papillary thyroid carcinoma managed at the Mayo Clinic during six decades (1940–1999): temporal trends in initial therapy and long-term outcome in 2444 consecutively treated patients. World J Surg 2002; 26: 879-885
• 4 Capella G, Matias-Guiu X, Ampudia X, de Leiva A, Perucho M, Prat J. Ras oncogene mutations in thyroid tumors: polymerase chain reaction-restriction-fragment-length polymorphism analysis from paraffin-embedded tissues. Diagn Mol Pathol 1996; 5: 45-52
• 5 Bongarzone I, Pierotti MA, Monzini N, Mondellini P, Manenti G, Donghi R, Pilotti S, Grieco M, Santoro M, Fusco A. High frequency of activation of tyrosine kinase oncogenes in human papillary thyroid carcinoma. Oncogene 1989; 4: 1457-1462
• 6 Giordano TJ, Kuick R, Thomas DG, Misek DE, Vinco M, Sanders D, Zhu Z, Ciampi R, Roh M, Shedden K, Gauger P, Doherty G, Thompson NW, Hanash S, Koenig RJ, Nikiforov YE. Molecular classification of papillary thyroid carcinoma: distinct BRAF, RAS, and RET/PTC mutation-specific gene expression profiles discovered by DNA microarray analysis. Oncogene 2005; 24: 6646-6656
• 7 Ciampi R, Knauf JA, Kerler R, Gandhi M, Zhu Z, Nikiforova MN, Rabes HM, Fagin JA, Nikiforov YE. Oncogenic AKAP9-BRAF fusion is a novel mechanism of MAPK pathway activation in thyroid cancer. J Clin Invest 2005; 115: 94-101
• 8 Kondo T, Ezzat S, Asa SL. Pathogenetic mechanisms in thyroid follicular-cell neoplasia. Nat Rev Cancer 2006; 6: 292-306
• 9 Liu Z, Hou P, Ji M, Guan H, Studeman K, Jensen K, Vasko V, El-Naggar AK, Xing M. Highly prevalent genetic alterations in receptor tyrosine kinases and phosphatidylinositol 3-kinase/akt and mitogen-activated protein kinase pathways in anaplastic and follicular thyroid cancers. J Clin Endocrinol Metab 2008; 93: 3106-3116
• 10 Santoro M, Carlomagno F, Hay ID, Herrmann MA, Grieco M, Melillo R, Pierotti MA, Bongarzone I, Della Porta G, Berger N. Ret oncogene activation in human thyroid neoplasms is restricted to the papillary cancer subtype. J Clin Invest 1992; 89: 1517-1522
• 11 Chevillard S, Ugolin N, Vielh P, Ory K, Levalois C, Elliott D, Clayman GL, El-Naggar AK. Gene expression profiling of differentiated thyroid neoplasms: diagnostic and clinical implications. Clin Cancer Res 2004; 10: 6586-6597
• 12 Crescenzi A, Guidobaldi L, Nasrollah N, Taccogna S, Cicciarella Modica DD, Turrini L, Nigri G, Romanelli F, Valabrega S, Giovanella L, Onetti Muda A, Trimboli P. Immunohistochemistry for BRAF(V600E) antibody VE1 performed in core needle biopsy samples identifies mutated papillary thyroid cancers. Horm Metab Res 2014; 46: 370-374
• 13 Cancer Genome Atlas Research Network. Integrated genomic characterization of papillary thyroid carcinoma. Cell 2014; 159: 676-690
• 14 Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, Davis AP, Dolinski K, Dwight SS, Eppig JT, Harris MA, Hill DP, Issel-Tarver L, Kasarskis A, Lewis S, Matese JC, Richardson JE, Ringwald M, Rubin GM, Sherlock G. Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat Genet 2000; 25: 25-29
• 15 Kanehisa M, Goto S. KEGG: kyoto encyclopedia of genes and genomes. Nucleic Acids Res 2000; 28: 27-30
• 16 Tabas-Madrid D, Nogales-Cadenas R, Pascual-Montano A. GeneCodis3: a non-redundant and modular enrichment analysis tool for functional genomics. Nucleic Acids Res 2012; 40: 478-483
• 17 Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, Amin N, Schwikowski B, Ideker T. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res 2003; 13: 2498-2504
• 18 Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011; 61: 69-90
• 19 Xing M. Molecular pathogenesis and mechanisms of thyroid cancer. Nat Rev Cancer 2013; 13: 184-199
• 20 Pita JM, Banito A, Cavaco BM, Leite V. Gene expression profiling associated with the progression to poorly differentiated thyroid carcinomas. Br J Cancer 2009; 101: 1782-1791
• 21 Giordano TJ, Au AY, Kuick R, Thomas DG, Rhodes DR, Wilhelm Jr KG, Vinco M, Misek DE, Sanders D, Zhu Z, Ciampi R, Hanash S, Chinnaiyan A, Clifton-Bligh RJ, Robinson BG, Nikiforov YE, Koenig RJ. Delineation, functional validation, and bioinformatic evaluation of gene expression in thyroid follicular carcinomas with the PAX8-PPARG translocation. Clin Cancer Res 2006; 12: 1983-1993
• 22 Dom G, Tarabichi M, Unger K, Thomas G, Oczko-Wojciechowska M, Bogdanova T, Jarzab B, Dumont JE, Detours V, Maenhaut C. A gene expression signature distinguishes normal tissues of sporadic and radiation-induced papillary thyroid carcinomas. Br J Cancer 2012; 107: 994-1000
• 23 Ruf J, Carayon P. Structural and functional aspects of thyroid peroxidase. Arch Biochem Biophys 2006; 445: 269-277
• 24 Doullay F, Ruf J, Codaccioni JL, Carayon P. Prevalence of autoantibodies to thyroperoxidase in patients with various thyroid and autoimmune diseases. Autoimmunity 1991; 9: 237-244
• 25 Bonetta L, Kuehn SE, Huang A, Law DJ, Kalikin LM, Koi M, Reeve AE, Brownstein BH, Yeger H, Williams BR. Wilms tumor locus on 11p13 defined by multiple CpG island-associated transcripts. Science 1990; 250: 994-997
• 26 Gessler M, Poustka A, Cavenee W, Neve RL, Orkin SH, Bruns GA. Homozygous deletion in Wilms tumours of a zinc-finger gene identified by chromosome jumping. Nature 1990; 343: 774-778
• 27 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: 249-260
• 28 Liguori L, Andolfo I, de Antonellis P, Aglio V, di Dato V, Marino N, Orlotti NI, De Martino D, Capasso M, Petrosino G, Schramm A, Navas L, Tonini GP, Eggert A, Iolascon A, Zollo M. The metallophosphodiesterase Mpped2 impairs tumorigenesis in neuroblastoma. Cell cycle 2012; 11: 569-581
• 29 Thedieck C, Kuczyk M, Klingel K, Steiert I, Muller CA, Klein G. Expression of Ksp-cadherin during kidney development and in renal cell carcinoma. Br J Cancer 2005; 92: 2010-2017
• 30 Wertz K, Herrmann BG. Kidney-specific cadherin (cdh16) is expressed in embryonic kidney, lung, and sex ducts. Mech Dev 1999; 84: 185-188
• 31 Strumane K, Berx G, Van Roy F. Cadherins in cancer. Handb Exp Pharmacol 2004; 165: 69-103
• 32 Berx G, van Roy F. Involvement of members of the cadherin superfamily in cancer. Cold Spring Harb Perspect Biol 2009; 1: a003129
• 33 Cali G, Gentile F, Mogavero S, Pallante P, Nitsch R, Ciancia G, Ferraro A, Fusco A, Nitsch L. CDH16/Ksp-cadherin is expressed in the developing thyroid gland and is strongly down-regulated in thyroid carcinomas. Endocrinology 2012; 153: 522-534
• 34 van Roy F, Berx G. The cell-cell adhesion molecule E-cadherin. Cell Mol Life Sci 2008; 65: 3756-3788
• 35 Xu Y, Deng Y, Ji Z, Liu H, Liu Y, Peng H, Wu J, Fan J. Identification of thyroid carcinoma related genes with mRMR and shortest path approaches. PLoS One 2014; 9: e94022
• 36 Zubakov D, Stupar Z, Kovacs G. Differential expression of a new isoform of DLG2 in renal oncocytoma. BMC Cancer 2006; 6: 106
• 37 Gallagher WM, Currid CA, Whelan LC. Fibulins and cancer: friend or foe?. Trends Mol Med 2005; 11: 336-340
• 38 Argraves WS, Greene LM, Cooley MA, Gallagher WM. Fibulins: physiological and disease perspectives. EMBO Rep 2003; 4: 1127-1131
• 39 Song EL, Hou YP, Yu SP, Chen SG, Huang JT, Luo T, Kong LP, Xu J, Wang HQ. EFEMP1 expression promotes angiogenesis and accelerates the growth of cervical cancer in vivo. Gynecol Oncol 2011; 121: 174-180
• 40 Seeliger H, Camaj P, Ischenko I, Kleespies A, De Toni EN, Thieme SE, Blum H, Assmann G, Jauch KW, Bruns CJ. EFEMP1 expression promotes in vivo tumor growth in human pancreatic adenocarcinoma. Mol Cancer Res 2009; 7: 189-198
• 41 Camaj P, Seeliger H, Ischenko I, Krebs S, Blum H, De Toni EN, Faktorova D, Jauch KW, Bruns CJ. EFEMP1 binds the EGF receptor and activates MAPK and Akt pathways in pancreatic carcinoma cells. Biol Chem 2009; 390: 1293-1302
• 42 Hwang CF, Chien CY, Huang SC, Yin YF, Huang CC, Fang FM, Tsai HT, Su LJ, Chen CH. Fibulin-3 is associated with tumour progression and a poor prognosis in nasopharyngeal carcinomas and inhibits cell migration and invasion via suppressed AKT activity. J Pathol 2010; 222: 367-379
• 43 Slany RK. The molecular biology of mixed lineage leukemia. Haematologica 2009; 94: 984-993
• 44 Maethner E, Garcia-Cuellar MP, Breitinger C, Takacova S, Divoky V, Hess JL, Slany RK. MLL-ENL inhibits polycomb repressive complex 1 to achieve efficient transformation of hematopoietic cells. Cell Rep 2013; 3: 1553-1566
• 45 Murphy AJ, Pierce J, de Caestecker C, Ayers GD, Zhao A, Krebs JR, Saito-Diaz VK, Lee E, Perantoni AO, de Caestecker MP, Lovvorn 3rd HN. CITED1 confers stemness to Wilms tumor and enhances tumorigenic responses when enriched in the nucleus. Oncotarget 2014; 5: 386-402
• 46 Tomas G, Tarabichi M, Gacquer D, Hebrant A, Dom G, Dumont JE, Keutgen X, Fahey 3rd TJ, 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: 4490-4498
• 47 Dom G, Tarabichi M, Unger K, Thomas G, Oczko-Wojciechowska M, Bogdanova T, Jarzab B, Dumont JE, Detours V, Maenhaut C. A gene expression signature distinguishes normal tissues of sporadic and radiation-induced papillary thyroid carcinomas. Br J Cancer 2012; 107: 994-1000