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BMC Cancer
Published in: BMC Cancer 1/2018

Open Access 01-12-2018 | Research article

CRABP1, C1QL1 and LCN2 are biomarkers of differentiated thyroid carcinoma, and predict extrathyroidal extension

Authors: Ricardo Celestino, Torfinn Nome, Ana Pestana, Andreas M. Hoff, A. Pedro Gonçalves, Luísa Pereira, Bruno Cavadas, Catarina Eloy, Trine Bjøro, Manuel Sobrinho-Simões, Rolf I. Skotheim, Paula Soares

Published in: BMC Cancer | Issue 1/2018

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Abstract

Background

The prognostic variability of thyroid carcinomas has led to the search for accurate biomarkers at the molecular level. Follicular thyroid carcinoma (FTC) is a typical example of differentiated thyroid carcinomas (DTC) in which challenges are faced in the differential diagnosis.

Methods

We used high-throughput paired-end RNA sequencing technology to study four cases of FTC with different degree of capsular invasion: two minimally invasive (mFTC) and two widely invasive FTC (wFTC). We searched by genes differentially expressed between mFTC and wFTC, in an attempt to find biomarkers of thyroid cancer diagnosis and/or progression. Selected biomarkers were validated by real-time quantitative PCR in 137 frozen thyroid samples and in an independent dataset (TCGA), evaluating the diagnostic and the prognostic performance of the candidate biomarkers.

Results

We identified 17 genes significantly differentially expressed between mFTC and wFTC. C1QL1, LCN2, CRABP1 and CILP were differentially expressed in DTC in comparison with normal thyroid tissues. LCN2 and CRABP1 were also differentially expressed in DTC when compared with follicular thyroid adenoma. Additionally, overexpression of LCN2 and C1QL1 were found to be independent predictors of extrathyroidal extension in DTC.

Conclusions

We conclude that the underexpression of CRABP1 and the overexpression of LCN2 may be useful diagnostic biomarkers in thyroid tumours with questionable malignity, and the overexpression of LCN2 and C1QL1 may be useful for prognostic purposes.
Appendix
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Literature
1.
Howlader N, Noone AM, Krapcho M, Neyman N, Aminou R, Waldron W, Altekruse SF, Kosary CL, Ruhl J, Tatalovich Z, Cho H, Mariotto A, Eisner MP, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). SEER Cancer Statistics Review, 1975-2009 (Vintage 2009 Populations), National Cancer Institute. Bethesda, MD, http://​seer.​cancer.​gov/​csr/​1975_​2009_​pops09/​, based on November 2011 SEER data submission, posted to the SEER web site, April 2012.
2.
Kondo T, Ezzat S, Asa SL. Pathogenetic mechanisms in thyroid follicular-cell neoplasia. Nat Rev Cancer. 2006;6:292–306.CrossRefPubMed
3.
DeLellis RA, Lloyd RV, Heitz PU, Eng C. WHO classification of Tumours. Pathology and Genetics of Tumours of Endocrine Organs. Lyon: IARC Press; 2004.
4.
Soares P, Celestino R, Melo M, Fonseca E, Sobrinho-Simoes M. Prognostic biomarkers in thyroid cancer. Virchows Arch. 2014;464:333–46.CrossRefPubMed
5.
Melo M, da Rocha AG, Vinagre J, Batista R, Peixoto J, Tavares C, Celestino R, Almeida A, Salgado C, Eloy C, et al. TERT promoter mutations are a major indicator of poor outcome in differentiated thyroid carcinomas. J Clin Endocrinol Metab. 2014;99:E754–765.
6.
Qureshi AA, Collins VP, Jani P. Genomic differences in benign and malignant follicular thyroid tumours using 1-Mb array-comparative genomic hybridisation. Eur Arch Otorhinolaryngol. 2013;270:325–35.CrossRefPubMed
7.
Sobrinho-Simoes M, Eloy C, Magalhaes J, Lobo C, Amaro T. Follicular thyroid carcinoma. Mod Pathol. 2011;24(Suppl 2):S10–8.CrossRefPubMed
8.
Collini P, Sampietro G, Rosai J, Pilotti S. Minimally invasive (encapsulated) follicular carcinoma of the thyroid gland is the low-risk counterpart of widely invasive follicular carcinoma but not of insular carcinoma. Virchows Arch. 2003;442:71–6.PubMed
9.
Cancer Genome Atlas Research. N. Integrated genomic characterization of papillary thyroid carcinoma. Cell. 2014;159:676–90.CrossRef
10.
Trapnell C, Williams BA, Pertea G, Mortazavi A, Kwan G, van Baren MJ, Salzberg SL, Wold BJ, Pachter L. Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation. Nat Biotechnol. 2010;28:511–5.CrossRefPubMedPubMedCentral
11.
12.
Celestino R, Sigstad E, Lovf M, Thomassen GO, Groholt KK, Jorgensen LH, Berner A, Castro P, Lothe RA, Bjoro T, et al. Survey of 548 oncogenic fusion transcripts in thyroid tumors supports the importance of the already established thyroid fusions genes. Genes Chromosomes Cancer. 2012;51(12):1154–64.CrossRefPubMed
13.
Vinagre J, Almeida A, Populo H, Batista R, Lyra J, Pinto V, Coelho R, Celestino R, Prazeres H, Lima L, et al. Frequency of TERT promoter mutations in human cancers. Nat Commun. 2013;4:2185.CrossRefPubMed
14.
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;25:402–8.CrossRefPubMed
15.
Cancer Genome Atlas Research Network. Integrated genomic characterization of papillary thyroid carcinoma. Cell. 2014;159(3):676–90.CrossRef
16.
17.
Giordano TJ, Au AY, Kuick R, Thomas DG, Rhodes DR, Wilhelm KG Jr, Vinco M, Misek DE, Sanders D, Zhu Z, 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.CrossRefPubMed
18.
He H, Jazdzewski K, Li W, Liyanarachchi S, Nagy R, Volinia S, Calin GA, Liu CG, Franssila K, Suster S, et al. The role of microRNA genes in papillary thyroid carcinoma. Proc Natl Acad Sci U S A. 2005;102:19075–80.CrossRefPubMedPubMedCentral
19.
Vasko V, Espinosa AV, Scouten W, He H, Auer H, Liyanarachchi S, Larin A, Savchenko V, Francis GL, de la Chapelle A, et al. Gene expression and functional evidence of epithelial-to-mesenchymal transition in papillary thyroid carcinoma invasion. Proc Natl Acad Sci U S A. 2007;104:2803–8.CrossRefPubMedPubMedCentral
20.
Leeman-Neill RJ, Kelly LM, Liu P, Brenner AV, Little MP, Bogdanova TI, Evdokimova VN, Hatch M, Zurnadzy LY, Nikiforova MN, et al. ETV6-NTRK3 is a common chromosomal rearrangement in radiation-associated thyroid cancer. Cancer. 2014;120:799–807.CrossRefPubMed
21.
Ricarte-Filho JC, Li S, Garcia-Rendueles ME, Montero-Conde C, Voza F, Knauf JA, Heguy A, Viale A, Bogdanova T, Thomas GA, et al. Identification of kinase fusion oncogenes in post-Chernobyl radiation-induced thyroid cancers. J Clin Invest. 2013;123:4935–44.CrossRefPubMedPubMedCentral
22.
Zhang Y, Yu J, Lee C, Xu B, Sartor MA, Koenig RJ. Genomic binding and regulation of gene expression by the thyroid carcinoma-associated PAX8-PPARG fusion protein. Oncotarget. 2015;6:40418–32.CrossRefPubMedPubMedCentral
23.
Smallridge RC, Chindris AM, Asmann YW, Casler JD, Serie DJ, Reddi HV, Cradic KW, Rivera M, Grebe SK, Necela BM, et al. RNA sequencing identifies multiple fusion transcripts, differentially expressed genes, and reduced expression of immune function genes in BRAF (V600E) mutant vs BRAF wild-type papillary thyroid carcinoma. J Clin Endocrinol Metab. 2014;99:E338–47.CrossRefPubMed
24.
Hawthorn L, Stein L, Varma R, Wiseman S, Loree T, Tan D. TIMP1 and SERPIN-A overexpression and TFF3 and CRABP1 underexpression as biomarkers for papillary thyroid carcinoma. Head Neck. 2004;26:1069–83.CrossRefPubMed
25.
Fontaine JF, Mirebeau-Prunier D, Raharijaona M, Franc B, Triau S, Rodien P, Goeau-Brissonniere O, Karayan-Tapon L, Mello M, Houlgatte R, et al. Increasing the number of thyroid lesions classes in microarray analysis improves the relevance of diagnostic markers. PLoS One. 2009;4:e7632.CrossRefPubMedPubMedCentral
26.
Huang Y, de la Chapelle A, Pellegata NS. Hypermethylation, but not LOH, is associated with the low expression of MT1G and CRABP1 in papillary thyroid carcinoma. Int J Cancer. 2003;104:735–44.CrossRefPubMed
27.
Berg M, Hagland HR, Soreide K. Comparison of CpG island methylator phenotype (CIMP) frequency in colon cancer using different probe- and gene-specific scoring alternatives on recommended multi-gene panels. PLoS One. 2014;9:e86657.CrossRefPubMedPubMedCentral
28.
Wang F, Yang Y, Fu Z, Xu N, Chen F, Yin H, Lu X, Shen R, Differential LC. DNA methylation status between breast carcinomatous and normal tissues. Biomed Pharmacother. 2014;
29.
Tanaka K, Imoto I, Inoue J, Kozaki K, Tsuda H, Shimada Y, Aiko S, Yoshizumi Y, Iwai T, Kawano T, Inazawa J. Frequent methylation-associated silencing of a candidate tumor-suppressor, CRABP1, in esophageal squamous-cell carcinoma. Oncogene. 2007;26:6456–68.CrossRefPubMed
30.
Kainov Y, Favorskaya I, Delektorskaya V, Chemeris G, Komelkov A, Zhuravskaya A, Trukhanova L, Zueva E, Tavitian B, Dyakova N, et al. CRABP1 provides high malignancy of transformed mesenchymal cells and contributes to the pathogenesis of mesenchymal and neuroendocrine tumors. Cell Cycle. 2014;13:1530–9.CrossRefPubMedPubMedCentral
31.
Miyake T, Ueda Y, Matsuzaki S, Miyatake T, Yoshino K, Fujita M, Nomura T, Enomoto T, Kimura T. CRABP1-reduced expression is associated with poorer prognosis in serous and clear cell ovarian adenocarcinoma. J Cancer Res Clin Oncol. 2011;137:715–22.CrossRefPubMed
32.
Seki S, Kawaguchi Y, Chiba K, Mikami Y, Kizawa H, Oya T, Mio F, Mori M, Miyamoto Y, Masuda I, et al. A functional SNP in CILP, encoding cartilage intermediate layer protein, is associated with susceptibility to lumbar disc disease. Nat Genet. 2005;37:607–12.CrossRefPubMed
33.
Chakraborty S, Kaur S, Guha S, Batra SK. The multifaceted roles of neutrophil gelatinase associated lipocalin (NGAL) in inflammation and cancer. Biochim Biophys Acta. 1826;2012:129–69.
34.
Iannetti A, Pacifico F, Acquaviva R, Lavorgna A, Crescenzi E, Vascotto C, Tell G, Salzano AM, Scaloni A, Vuttariello E, et al. The neutrophil gelatinase-associated lipocalin (NGAL), a NF-kappaB-regulated gene, is a survival factor for thyroid neoplastic cells. Proc Natl Acad Sci U S A. 2008;105:14058–63.CrossRefPubMedPubMedCentral
35.
Volpe V, Raia Z, Sanguigno L, Somma D, Mastrovito P, Moscato F, Mellone S, Leonardi A, Pacifico FNGAL. Controls the metastatic potential of anaplastic thyroid carcinoma cells. J Clin Endocrinol Metab. 2013;98:228–35.CrossRefPubMed
36.
Iijima T, Miura E, Watanabe M, Yuzaki M. Distinct expression of C1q-like family mRNAs in mouse brain and biochemical characterization of their encoded proteins. Eur J Neurosci. 2010;31:1606–15.PubMed
37.
Alexander EK, Kennedy GC, Baloch ZW, Cibas ES, Chudova D, Diggans J, Friedman L, Kloos RT, LiVolsi VA, Mandel SJ, et al. Preoperative diagnosis of benign thyroid nodules with indeterminate cytology. N Engl J Med. 2012;367:705–15.CrossRefPubMed
38.
Alexander EK, Schorr M, Klopper J, Kim C, Sipos J, Nabhan F, Parker C, Steward DL, Mandel SJ, Haugen BR. Multicenter clinical experience with the Afirma gene expression classifier. J Clin Endocrinol Metab. 2014;99:119–25.CrossRefPubMed
39.
Nikiforov YE, Carty SE, Chiosea SI, Coyne C, Duvvuri U, Ferris RL, Gooding WE, LeBeau SO, Ohori NP, Seethala RR, et al. Impact of the multi-gene ThyroSeq next-generation sequencing assay on cancer diagnosis in thyroid nodules with atypia of undetermined significance/follicular lesion of undetermined significance cytology. Thyroid. 2015;25:1217–23.CrossRefPubMedPubMedCentral
40.
Nikiforov YE, Carty SE, Chiosea SI, Coyne C, Duvvuri U, Ferris RL, Gooding WE, Hodak SP, LeBeau SO, Ohori NP, et al. 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.CrossRefPubMed
41.
McIver B, Castro MR, Morris JC, Bernet V, Smallridge R, Henry M, Kosok L, Reddi H. An independent study of a gene expression classifier (Afirma) in the evaluation of cytologically indeterminate thyroid nodules. J Clin Endocrinol Metab. 2014;99:4069–77.CrossRefPubMed
42.
Kargi AY, Bustamante MP, Gulec S. Genomic profiling of thyroid nodules: current role for ThyroSeq next-generation sequencing on clinical decision-making. Mol Imaging Radionucl Ther. 2017;26:24–35.CrossRefPubMedPubMedCentral
Metadata
Title
CRABP1, C1QL1 and LCN2 are biomarkers of differentiated thyroid carcinoma, and predict extrathyroidal extension
Authors
Ricardo Celestino
Torfinn Nome
Ana Pestana
Andreas M. Hoff
A. Pedro Gonçalves
Luísa Pereira
Bruno Cavadas
Catarina Eloy
Trine Bjøro
Manuel Sobrinho-Simões
Rolf I. Skotheim
Paula Soares
Publication date
01-12-2018
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2018
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-017-3948-3

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