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Gene Expression Patterns Unveil New Insights in Papillary Thyroid Cancer.

ABSTRACT: Background and objectives: Papillary thyroid carcinoma is the most frequent variety of all malignant endocrine tumors. It represents a heterogeneous malignancy with various clinical outcomes, emphasizing the need to identify powerful biomarkers with clinical relevance. Materials and Methods: Available gene expression data (level 3) for thyroid cancers were downloaded from the Cancer Genome Atlas (TCGA), followed by bioinformatic analyses performed on the data set. Results: Based on gene expression analysis, we were able to identify common and specific gene signatures for the three main types of papillary thyroid carcinoma (classical, follicular variant, and tall-cell). The survival rate was not significantly different among the main subtypes, but we were able to identify a biological adhesion signature with impact in patient prognostic. Conclusions: Taken together, the gene expression signature and particular adhesion signature, along with ITGA10 and MSLN in particular, could be used as a prognostic tool with important clinical relevance.

SUBMITTER: Saftencu M

PROVIDER: S-EPMC6723230 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Gene Expression Patterns Unveil New Insights in Papillary Thyroid Cancer.

Saftencu Mihai M Braicu Cornelia C Cojocneanu Roxana R Buse Mihail M Irimie Alexandru A Piciu Doina D Berindan-Neagoe Ioana I

Medicina (Kaunas, Lithuania) 20190819 8

Background and objectives: Papillary thyroid carcinoma is the most frequent variety of all malignant endocrine tumors. It represents a heterogeneous malignancy with various clinical outcomes, emphasizing the need to identify powerful biomarkers with clinical relevance. Materials and Methods: Available gene expression data (level 3) for thyroid cancers were downloaded from the Cancer Genome Atlas (TCGA), followed by bioinformatic analyses performed on the data set. Results ...[more]

PMID: 31430969

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Project description:The recognition that colorectal cancer (CRC) is a heterogeneous disease in terms of clinical behaviour and response to therapy translates into an urgent need for robust molecular disease subclassifiers that can explain this heterogeneity beyond current parameters (MSI, KRAS, BRAF). Attempts to fill this gap are emerging. The Cancer Genome Atlas (TGCA) reported two main CRC groups, based on the incidence and spectrum of mutated genes, and another paper reported an EMT expression signature defined subgroup. We performed a prior free analysis of CRC heterogeneity on 1113 CRC gene expression profiles and confronted our findings to established molecular determinants and clinical, histopathological and survival data. Unsupervised clustering based on gene modules allowed us to distinguish at least five different gene expression CRC subtypes, which we call surface crypt-like, lower crypt-like, CIMP-H-like, mesenchymal and mixed. A gene set enrichment analysis combined with literature search of gene module members identified distinct biological motifs in different subtypes. The subtypes, which were not derived based on outcome, nonetheless showed differences in prognosis. Known gene copy number variations and mutations in key cancer-associated genes differed between subtypes, but the subtypes provided molecular information beyond that contained in these variables. Morphological features significantly differed between subtypes. The objective existence of the subtypes and their clinical and molecular characteristics were validated in an independent set of 720 CRC expression profiles. Our subtypes provide a novel perspective on the heterogeneity of CRC. The proposed subtypes should be further explored retrospectively on existing clinical trial datasets and, when sufficiently robust, be prospectively assessed for clinical relevance in terms of prognosis and treatment response predictive capacity. Original microarray data were uploaded to the ArrayExpress database (http://www.ebi.ac.uk/arrayexpress/) under Accession Nos E-MTAB-990 and E-MTAB-1026.

Project description:BACKGROUND:FOXE1, a thyroid-specific transcription factor also known as TTF-2, was recently identified as a major genetic risk factor for papillary thyroid carcinoma (PTC). Its role in thyroid carcinogenesis, however, remains unknown. The purpose of the present study was to assess the relationship between the FOXE1 immunohistochemical features and the clinical and genetic characteristics of PTC. METHODS:Immunohistochemical staining of FOXE1 was performed in 48 PTC cases. Two single nucleotide polymorphisms immediately inside (rs1867277) or in the vicinity (rs965513) of the FOXE1 gene were genotyped by direct sequencing. Histopathological, clinical, and genetic data were included in statistical analyses. RESULTS:FOXE1 exhibited cytoplasmic overexpression in tumor tissue compared to the normal counterpart (p<0.001). Both cancer and normal thyroid cells demonstrated the highest FOXE1 scores in the areas closest to the tumor border (<300 ?m) compared with more distant areas (p<0.001). No differences in FOXE1 staining distributions were found between microcarcinomas and PTC of larger size, between different histopathological variants of PTC, and encapsulated and nonencapsulated tumors. Multivariate regression analysis revealed that nuclear FOXE1 expression in neoplastic cells in the vicinity of the tumor border independently associated with the genotype at rs1867277 (the dominant model of inheritance, p=0.037) and tumor multifocality (p=0.032), and with marginal significance with capsular invasion (p=0.051). CONCLUSIONS:FOXE1 overexpression and translocation to the cytoplasm are phenotypic hallmarks of tumor cells suggesting that FOXE1 is involved in the pathogenesis of PTC. Nuclear FOXE1 expression in tumor cells in the vicinity of the PTC border is associated with the presence of a risk allele of rs1867277 (c.-238G>A) in the 5' untranslated region of the FOXE1 gene, as well as with pathological characteristics of PTC, suggesting possible FOXE1 involvement in the facilitation of tumor development beginning at an early stage.

Project description:BACKGROUND:Papillary thyroid cancer (PTC) is the most frequent endocrine tumor. Radioiodine (RAI) treatment is highly effective in these tumors, but up to 60% of metastatic cases become RAI-refractory. Scanty data are available on either the molecular pattern of radioiodine refractory papillary thyroid cancers (PTC) or the mechanisms responsible for RAI resistance. METHODS:We analyzed the molecular profile and gene/miRNA expression in primary PTCs, synchronous and RAI-refractory lymph node metastases (LNMs) in correlation to RAI avidity or refractoriness. We classified patients as RAI+/D+ (RAI uptake/disease persistence), RAI-/D+ (absent RAI uptake/disease persistence), and RAI+/D- (RAI uptake/disease remission), and analyzed the molecular and gene/miRNA profiles, and the expression of thyroid differentiation (TD) related genes. RESULTS:A different molecular profile according to the RAI class was observed: BRAFV600E cases were more frequent in RAI-/D+ (P?=?0.032), and fusion genes in RAI+/D+ cases. RAI+/D- patients were less frequently pTERT mutations positive, and more frequently wild type for the tested mutations/fusions. Expression profiles clearly distinguished PTC from normal thyroid. On the other hand, in refractory cases (RAI+/D+ and RAI-/D+) no distinctive PTC expression patterns were associated with either tissue type, or RAI uptake, but with the driving lesion and BRAF-/RAS-like subtype. Primary tumors and RAI-refractory LNMs with BRAFV600E mutation display transcriptome similarity suggesting that RAI minimally affects the expression profiles of RAI-refractory metastases. Molecular profiles associated with the expression of TPO, SLC26A4 and TD genes, that were found more downregulated in BRAFV600E than in gene fusions tumors. CONCLUSIONS:The present data indicate a different molecular profile in RAI-avid and RAI-refractory metastatic PTCs. Moreover, BRAFV600E tumors displayed reduced differentiation and intrinsic RAI refractoriness, while PTCs with fusion oncogenes are RAI-avid but persistent, suggesting different oncogene-driven mechanisms leading to RAI refractoriness.

Project description:BackgroundAlthough the most thyroid carcinoma patients have good prognosis, around 20% of papillary thyroid carcinoma (PTC) patients have a high rate of metastasis and recurrence after routine treatment, which causes high lethality with these patients. Tumor proliferation, metastasis, and invasion are important predictors of PTC invasiveness and are key factors in cancer-related death. Angiopoietin-like 2 (ANGPTL2), a secreted protein which belongs to the angiopoietin (ANGPTL) family, was reported to be involved in the regulation of several different type of cancer cell proliferation and metastasis. However, whether ANGPTL2 plays a role in the progression of PTC, particularly in metastasis and recurrence of PTC, remains unclear. Hence, the purpose of this study was to evaluate the level of ANGPTL2 in PTC and normal thyroid, as well as para-cancerous tissue. Furthermore, the impact of ANGPTL2 on PTC cell proliferation, metastasis, recurrence and invasion was assessed to investigate the possibility whether ANGPTL2 may become a novel target for PTC therapy and cancer prognosis.Materials and methodsThe level of ANGPTL2 in PTC and para-cancerous tissue was assessed by immunohistochemistry. The biological effect of ANGPTL2 on thyroid cancer cell proliferation and metastasis was investigated by the Cell Counting Kit-8 (CCK8) assay, cell scratch test, and transwell assay. Correlations of ANGPTL2 expression levels with proliferation, migration, and metastasis of thyroid cancer were assessed with the TCGA data set and analyzed by gene set enrichment analysis. Receiver operating characteristic analysis was used to evaluate the utility of ANGPTL2 as a biomarker for prediction of thyroid cancer. Survival analysis was performed using the thyroid cancer database in K-M Plotter to detect correlations between survival time and ANGPTL2 levels.ResultsCurrent study revealed that: (1) ANGPTL2 was highly expressed in thyroid cancer in comparison with adjacent normal thyroid tissue; (2) ANGPTL2 expression was increased with thyroid tumor progression; (3) ANGPTL2 increased proliferation of thyroid cancer cells; (4) ANGPTL2 promoted migration and invasion of thyroid cancer cells; (5) high level of ANGPTL2 in thyroid cancer patients were significantly associated with a poor prognosis. The patients showed a higher metastasis and recurrence rate.ConclusionANGPTL2 promoted and enhanced proliferation, metastasis, and invasion of thyroid cancer cells. ANGPTL2 may be considered as a potential biomarker for diagnosis and prognosis of thyroid cancer patients. Further evaluation needs to be done to analyze the possibility of taking ANGPTL2 as a prognostic marker and therapeutic target for papillary thyroid cancer.

Dataset Information

Gene Expression Patterns Unveil New Insights in Papillary Thyroid Cancer.

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Gene Expression Patterns Unveil New Insights in Papillary Thyroid Cancer.

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