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Current Bioinformatics

Editor-in-Chief

ISSN (Print): 1574-8936
ISSN (Online): 2212-392X

Research Article

Construction of an Expression Classifier Based on an Immune-related Ten-gene Panel for Rapid Diagnosis of Papillary Thyroid Carcinoma Risks

Author(s): Jingxue Sun, Jingjing Li, Yaguang Zhang, Jun Han, Jiaxing Wei, Yanmeizhi Wu, Bing Liu, Hongyu Han and Hong Qiao*

Volume 17, Issue 10, 2022

Published on: 10 October, 2022

Page: [924 - 936] Pages: 13

DOI: 10.2174/1574893617666220615123729

Price: $65

Abstract

Background: Molecular alterations have been recognized as valuable diagnostic biomarkers for papillary thyroid carcinoma (PTC).

Objectives: This study aimed to identify immune-related gene signatures associated with PTC progression using a computational pipeline and to develop an expression-based panel for rapid PTC risk classification.

Methods: RNA-seq data and clinical information for PTC samples were downloaded from The Cancer Genome Atlas, followed by an analysis of differentially expressed (DE) RNAs among high-risk PTC, low-risk PTC, and normal groups. Immune cell infiltration and protein–protein interaction analyses were performed to obtain DE RNAs related to immunity. Then, a competing endogenous RNA (ceRNA) network was constructed to identify hub genes for the construction of a diagnostic model, which was evaluated by a receiver operator characteristic curve. A manually curated independent sample cohort was constructed to validate the model.

Results: By analyzing the immune cell infiltration, we found that the infiltration of plasma cells and CD8+ T cells was more abundant in the high-risk groups, and 68 DE mRNAs were found to be significantly correlated with these immune cells. Then a ceRNA network containing 10 immune-related genes was established. The ten-gene panel (including DEPDC1B, ELF3, VWA1, CXCL12, SLC16A2, C1QC, IPCEF1, ITM2A, UST, and ST6GAL1) was used to construct a diagnostic model with specificity (66.3%), sensitivity (83.3%), and area under the curve (0.762) for PTC classification. DEPDC1B and SLC16A2 were experimentally validated to be differentially expressed between high-risk and low-risk patients.

Conclusion: The 10 immune-related gene panels can be used to evaluate the risk of PTC during pointof- care testing with high specificity and sensitivity.

Keywords: papillary thyroid carcinoma, immune-related gene panel, diagnostic model, risk classification, ceRNA regulatory network, SLC16A2, DEPDC1B

Graphical Abstract

[1]
Lamartina L, Grani G, Durante C, Borget I, Filetti S, Schlumberger M. Follow-up of differentiated thyroid cancer - what should (and what should not) be done. Nat Rev Endocrinol 2018; 14(9): 538-51.
[http://dx.doi.org/10.1038/s41574-018-0068-3] [PMID: 30069030]
[2]
Doja MN, Kaur I, Ahmad T. Current state of the art for survival prediction in cancer using data mining techniques. Curr Bioinform 2020; 15(3): 174-86.
[http://dx.doi.org/10.2174/1574893614666190902152142]
[3]
Yang J, Peng S, Zhang B, et al. Human geroprotector discovery by targeting the converging subnetworks of aging and age-related diseases. Geroscience 2020; 42(1): 353-72.
[http://dx.doi.org/10.1007/s11357-019-00106-x] [PMID: 31637571]
[4]
Ma X, Baohang X, Yi Z, et al. A machine learning-based diagnosis of thyroid cancer using thyroid nodules ultrasound images. Curr Bioinform 2020; 15(4): 349-58.
[http://dx.doi.org/10.2174/1574893614666191017091959]
[5]
Vaccarella S, Franceschi S, Bray F, Wild CP, Plummer M, Dal Maso L. Worldwide thyroid-cancer epidemic? The increasing impact of overdiagnosis. N Engl J Med 2016; 375(7): 614-7.
[http://dx.doi.org/10.1056/NEJMp1604412] [PMID: 27532827]
[6]
Archana E, Vijayakumar C, Raj Kumar N, et al. A comparative study of fine-needle aspiration and nonaspiration cytology diagnosis in thyroid lesions. Niger J Surg 2020; 26(2): 147-52.
[PMID: 33223814]
[7]
Prete A, Borges de Souza P, Censi S, Muzza M, Nucci N, Sponziello M. Update on fundamental mechanisms of thyroid cancer. Front Endocrinol (Lausanne) 2020; 11: 102.
[http://dx.doi.org/10.3389/fendo.2020.00102] [PMID: 32231639]
[8]
Bergdorf K, Ferguson DC, Mehrad M, Ely K, Stricker T, Weiss VL. Papillary thyroid carcinoma behavior: Clues in the tumor microenvironment. Endocr Relat Cancer 2019; 26(6): 601-14.
[http://dx.doi.org/10.1530/ERC-19-0074] [PMID: 30965283]
[9]
Liu H, Qiu C, Wang B, et al. Evaluating DNA methylation, gene expression, somatic mutation, and their combinations in inferring tumor tissue-of-origin. Front Cell Dev Biol 2021; 9: 619330.
[http://dx.doi.org/10.3389/fcell.2021.619330] [PMID: 34012960]
[10]
He B, Lang J, Wang B, et al. TOOme: A novel computational framework to infer cancer tissue-of-origin by integrating both gene mutation and expression. Front Bioeng Biotechnol 2020; 8: 394.
[http://dx.doi.org/10.3389/fbioe.2020.00394] [PMID: 32509741]
[11]
He B, Dai C, Lang J, et al. A machine learning framework to trace tumor tissue-of-origin of 13 types of cancer based on DNA somatic mutation. Biochim Biophys Acta Mol Basis Dis 2020; 1866(11): 165916.
[http://dx.doi.org/10.1016/j.bbadis.2020.165916] [PMID: 32771416]
[12]
American Joint Committee on Cancer. AJCC cancer staging manual. In: Frederick LG, David LP, Irvin DF, April GF, Charles MB, Daniel GH, Monica M 6th ed. New York, NY: Springer 2002; p. XV, 421..
[http://dx.doi.org/10.1007/978-1-4757-3656-4]
[13]
Mazzaferri EL, Jhiang SM. Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer. Am J Med 1994; 97(5): 418-28.
[http://dx.doi.org/10.1016/0002-9343(94)90321-2] [PMID: 7977430]
[14]
Berdelou A, Lamartina L, Klain M, Leboulleux S, Schlumberger M. Treatment of refractory thyroid cancer. Endocr Relat Cancer 2018; 25(4): R209-23.
[http://dx.doi.org/10.1530/ERC-17-0542] [PMID: 29371330]
[15]
Grani G, Lamartina L, Durante C, Filetti S, Cooper DS. Follicular thyroid cancer and Hürthle cell carcinoma: Challenges in diagnosis, treatment, and clinical management. Lancet Diabetes Endocrinol 2018; 6(6): 500-14.
[http://dx.doi.org/10.1016/S2213-8587(17)30325-X] [PMID: 29102432]
[16]
Hay ID, Johnson TR, Kaggal S, et al. Papillary Thyroid Carcinoma (PTC) in children and adults: Comparison of initial presentation and long-term postoperative outcome in 4432 patients consecutively treated at the mayo clinic during eight decades (1936-2015). World J Surg 2018; 42(2): 329-42.
[http://dx.doi.org/10.1007/s00268-017-4279-x] [PMID: 29030676]
[17]
Shaha AR, Shah JP, Loree TR. Low-risk differentiated thyroid cancer: The need for selective treatment. Ann Surg Oncol 1997; 4(4): 328-33.
[http://dx.doi.org/10.1007/BF02303583] [PMID: 9181233]
[18]
Krajewska J, Kukulska A, Oczko-Wojciechowska M, et al. Early diagnosis of low-risk papillary thyroid cancer results rather in overtreatment than a better survival. Front Endocrinol (Lausanne) 2020; 11: 571421.
[http://dx.doi.org/10.3389/fendo.2020.571421] [PMID: 33123090]
[19]
Kunavisarut T. Diagnostic biomarkers of differentiated thyroid cancer. Endocrine 2013; 44(3): 616-22.
[http://dx.doi.org/10.1007/s12020-013-9974-2] [PMID: 23645523]
[20]
Kim K, Jeon S, Kim TM, Jung CK. Immune gene signature delineates a subclass of papillary thyroid cancer with unfavorable clinical outcomes. Cancers (Basel) 2018; 10(12): E494.
[http://dx.doi.org/10.3390/cancers10120494] [PMID: 30563160]
[21]
Goldman M, et al. The UCSC Xena platform for public and private cancer genomics data visualization and interpretation. bioRxiv 2019; 326470.
[22]
Harrow J, Frankish A, Gonzalez JM, et al. GENCODE: The reference human genome annotation for The ENCODE Project. Genome Res 2012; 22(9): 1760-74.
[http://dx.doi.org/10.1101/gr.135350.111] [PMID: 22955987]
[23]
Smyth GK. limma: Linear Models for Microarray Data. In: Gentleman R, Ed. Bioinformatics and Computational Biology Solutions Using R and Bioconductor. New York, NY: Springer New York 2005; pp. 397-420.
[24]
Newman AM, Liu CL, Green MR, et al. Robust enumeration of cell subsets from tissue expression profiles. Nat Methods 2015; 12(5): 453-7.
[http://dx.doi.org/10.1038/nmeth.3337] [PMID: 25822800]
[25]
Keshava Prasad TS, Goel R, Kandasamy K, et al. Human protein reference database--2009 update. Nucleic Acids Res 2009; 37(Database issue): D767-72.
[http://dx.doi.org/10.1093/nar/gkn892] [PMID: 18988627]
[26]
Shannon P, Markiel A, Ozier O, et al. Cytoscape: A software environment for integrated models of biomolecular interaction networks. Genome Res 2003; 13(11): 2498-504.
[http://dx.doi.org/10.1101/gr.1239303] [PMID: 14597658]
[27]
Yang J, Huang T, Song WM, et al. Discover the network underlying the connections between aging and age-related diseases. Sci Rep 2016; 6: 32566.
[http://dx.doi.org/10.1038/srep32566] [PMID: 27582315]
[28]
Dweep H, Gretz N. miRWalk2.0: A comprehensive atlas of microRNA-target interactions. Nat Methods 2015; 12(8): 697.
[http://dx.doi.org/10.1038/nmeth.3485] [PMID: 26226356]
[29]
Paraskevopoulou MD, Vlachos IS, Karagkouni D, et al. DIANA-LncBase v2: Indexing microRNA targets on non-coding transcripts. Nucleic Acids Res 2016; 44(D1): D231-8.
[http://dx.doi.org/10.1093/nar/gkv1270] [PMID: 26612864]
[30]
Liu S, Hailin T, Hongde L, Jinke W. Multi-label learning for diagnosis of cancer and identification of novel biomarkers with high-throughput omics. Curr Bioinform 2020; 15: 261-73.
[32]
Dong YM, Jia-hao B, Qi-en H, Kai S. ESDA: An improved approach to accurately identify human snoRNAs for precision cancer therapy. Curr Bioinform 2020; 15(1): 34-40.
[http://dx.doi.org/10.2174/1574893614666190424162230]
[33]
Uhlen M, Zhang C, Sunjee L, et al. A pathology atlas of the human cancer transcriptome. Science 2017; 357(6352)
[http://dx.doi.org/10.1126/science.aan2507]
[34]
Gu Y, Ying G, Xiaodan T, Huizhong X, Kunhe S. Bioinformatics analysis identifies CPZ as a tumor immunology biomarker for gastric cancer. Curr Bioinform 2020; 15(1): 98-105.
[http://dx.doi.org/10.2174/1574893615999200707145643]
[35]
Joyce JA, Fearon DT. T cell exclusion, immune privilege, and the tumor microenvironment. Science 2015; 348(6230): 74-80.
[http://dx.doi.org/10.1126/science.aaa6204] [PMID: 25838376]
[36]
Crespo J, Sun H, Welling TH, Tian Z, Zou W. T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment. Curr Opin Immunol 2013; 25(2): 214-21.
[http://dx.doi.org/10.1016/j.coi.2012.12.003] [PMID: 23298609]
[37]
Chen L, Li J, Chang M. Cancer diagnosis and disease gene identification via statistical machine learning. Curr Bioinform 2020; 15(9)
[http://dx.doi.org/10.2174/1574893615666200207094947]
[38]
Jaillon S, Galdiero MR, Del PD, et al. Neutrophils in innate and adaptive immunity. In: Seminars in immunopathology. Semin Immunopathol 2013; 35: 377-94.
[http://dx.doi.org/10.1007/s00281-013-0374-8]
[39]
Lee EK, Sunwoo JB. Natural killer cells and thyroid diseases. Endocrinol Metab (Seoul) 2019; 34(2): 132-7.
[http://dx.doi.org/10.3803/EnM.2019.34.2.132] [PMID: 31257741]
[40]
Cunha LL, Morari EC, Guihen AC, et al. Infiltration of a mixture of immune cells may be related to good prognosis in patients with differentiated thyroid carcinoma. Clin Endocrinol (Oxf) 2012; 77(6): 918-25.
[http://dx.doi.org/10.1111/j.1365-2265.2012.04482.x] [PMID: 22738343]
[41]
Kohlgraf KG, Gawron AJ, Higashi M, et al. Contribution of the MUC1 tandem repeat and cytoplasmic tail to invasive and metastatic properties of a pancreatic cancer cell line. Cancer Res 2003; 63(16): 5011-20.
[PMID: 12941828]
[42]
Hollingsworth MA, Swanson BJ. Mucins in cancer: Protection and control of the cell surface. Nat Rev Cancer 2004; 4(1): 45-60.
[http://dx.doi.org/10.1038/nrc1251] [PMID: 14681689]
[43]
Liu J, Lian X, Lui F, et al. Identification of novel key targets and candidate drugs in oral squamous cell carcinoma. Curr Bioinform 2020; 15(1): 328-37.
[http://dx.doi.org/10.2174/1574893614666191127101836]
[44]
Patel KN, Maghami E, Wreesmann VB, et al. MUC1 plays a role in tumor maintenance in aggressive thyroid carcinomas. Surgery 2005; 138(6): 994-1001.
[http://dx.doi.org/10.1016/j.surg.2005.09.030] [PMID: 16360383]
[45]
Oleksiewicz U, Liloglou T, Tasopoulou KM, et al. COL1A1, PRPF40A, and UCP2 correlate with hypoxia markers in non-small cell lung cancer. J Cancer Res Clin Oncol 2017; 143(7): 1133-41.
[http://dx.doi.org/10.1007/s00432-017-2381-y] [PMID: 28258342]
[46]
Lv J, Guo L, Wang JH, et al. Biomarker identification and trans-regulatory network analyses in esophageal adenocarcinoma and Barrett’s esophagus. World J Gastroenterol 2019; 25(2): 233-44.
[http://dx.doi.org/10.3748/wjg.v25.i2.233] [PMID: 30670912]
[47]
Huang C, Yang X, Han L, et al. The prognostic potential of alpha-1 type I collagen expression in papillary thyroid cancer. Biochem Biophys Res Commun 2019; 515(1): 125-32.
[http://dx.doi.org/10.1016/j.bbrc.2019.04.119] [PMID: 31128912]
[48]
Werner TA, Forster CM, Dizdar L, et al. CXCR4/CXCR7/CXCL12 axis promotes an invasive phenotype in medullary thyroid carcinoma. Br J Cancer 2017; 117(12): 1837-45.
[http://dx.doi.org/10.1038/bjc.2017.364] [PMID: 29112684]
[49]
Zhi Y, Chen J, Zhang S, Chang X, Ma J, Dai D. Down-regulation of CXCL12 by DNA hypermethylation and its involvement in gastric cancer metastatic progression. Dig Dis Sci 2012; 57(3): 650-9.
[http://dx.doi.org/10.1007/s10620-011-1922-5] [PMID: 21960286]
[50]
Zhao Z. Integrative analysis of miRNA-mediated competing endogenous RNA network reveals the lncRNAs-mRNAs interaction in glioblastoma stem cell differentiation 2020; 15
[51]
Lu M, Xu X, Xi B, et al. Molecular network-based identification of competing endogenous RNAs in thyroid carcinoma. Genes (Basel) 2018; 9(1): E44.
[http://dx.doi.org/10.3390/genes9010044] [PMID: 29351231]
[52]
de Oliveira JC, Oliveira LC, Mathias C, et al. Long non-coding RNAs in cancer: Another layer of complexity. J Gene Med 2019; 21(1): e3065.
[PMID: 30549380]
[53]
Sun Y, Chen L, Zhang Y, Zhang J, Tiwari SR. Genome-wide identification of differently expressed lncRNAs, mRNAs, and circRNAs in patients with osteoarthritis. Curr Bioinform 2020; 15(10): 1222-30.
[54]
Yuan J, Song Y, Pan W, et al. LncRNA SLC26A4-AS1 suppresses the MRN complex-mediated DNA repair signaling and thyroid cancer metastasis by destabilizing DDX5. Oncogene 2020; 39(43): 6664-76.
[http://dx.doi.org/10.1038/s41388-020-01460-3] [PMID: 32939012]
[55]
Xu X, Long H, Xi B, et al. Molecular network-based drug prediction in thyroid cancer. Int J Mol Sci 2019; 20(2): E263.
[http://dx.doi.org/10.3390/ijms20020263] [PMID: 30641858]
[56]
Ye S, Liang Y, Zhang BJCB. Bayesian functional mixed-effects models with grouped smoothness for analyzing time-course gene expression data. Curr Bioinform 2021; 16(1): 2-12.
[57]
Hong S, Yu S, Li J, et al. MiR-20b displays tumor-suppressor functions in papillary thyroid carcinoma by regulating the MAPK/ERK signaling pathway. Thyroid 2016; 26(12): 1733-43.
[http://dx.doi.org/10.1089/thy.2015.0578] [PMID: 27717302]
[58]
Boufraqech M, Patel D, Xiong Y, Kebebew E. Diagnosis of thyroid cancer: State of art. Expert Opin Med Diagn 2013; 7(4): 331-42.
[http://dx.doi.org/10.1517/17530059.2013.800481] [PMID: 23701167]
[59]
Beaudenon-Huibregtse S, Alexander EK, Guttler RB, et al. Centralized molecular testing for oncogenic gene mutations complements the local cytopathologic diagnosis of thyroid nodules. Thyroid 2014; 24(10): 1479-87.
[http://dx.doi.org/10.1089/thy.2013.0640] [PMID: 24811481]
[60]
Alexander EK, Kennedy GC, Baloch ZW, et al. Preoperative diagnosis of benign thyroid nodules with indeterminate cytology. N Engl J Med 2012; 367(8): 705-15.
[http://dx.doi.org/10.1056/NEJMoa1203208] [PMID: 22731672]
[61]
Chudova D, Wilde JI, Wang ET, et al. Molecular classification of thyroid nodules using high-dimensionality genomic data. J Clin Endocrinol Metab 2010; 95(12): 5296-304.
[http://dx.doi.org/10.1210/jc.2010-1087] [PMID: 20826580]
[62]
Lai CH, Xu K, Zhou J, et al. DEPDC1B is a tumor promotor in development of bladder cancer through targeting SHC1. Cell Death Dis 2020; 11(11): 986.
[http://dx.doi.org/10.1038/s41419-020-03190-6] [PMID: 33203836]
[63]
Bai S, Chen T, Du T, et al. High levels of DEPDC1B predict shorter biochemical recurrence-free survival of patients with prostate cancer. Oncol Lett 2017; 14(6): 6801-8.
[http://dx.doi.org/10.3892/ol.2017.7027] [PMID: 29163701]
[64]
Xu N, Chen J, He G, Gao L, Zhang D. Prognostic values of m6A RNA methylation regulators in differentiated thyroid carcinoma. J Cancer 2020; 11(17): 5187-97.
[http://dx.doi.org/10.7150/jca.41193] [PMID: 32742465]
[65]
Xu J, Cai L, Liao B, Zhu W, Yang J. CMF-Impute: An accurate imputation tool for single-cell RNA-seq data. Bioinformatics 2020; 36(10): 3139-47.
[http://dx.doi.org/10.1093/bioinformatics/btaa109] [PMID: 32073612]
[66]
Zhuang J. A streamlined scRNA-Seq data analysis framework based on improved sparse subspace clustering. IEEE Access 2021; 99: 1-1.
[http://dx.doi.org/10.1109/ACCESS.2021.3049807]

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