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Papillary Thyroid Carcinoma Variants are Characterized by Co-dysregulation of Immune and Cancer Associated Genes.

ABSTRACT: Papillary thyroid carcinoma (PTC) variants exhibit different prognosis, but critical characteristics of PTC variants that contribute to differences in pathogenesis are not well-known. This study aims to characterize dysregulated immune-associated and cancer-associated genes in three PTC subtypes to explore how the interplay between cancer and immune processes causes differential prognosis. RNA-sequencing data from The Cancer Genome Atlas (TCGA) were used to identify dysregulated genes in each variant. The dysregulation profiles of the subtypes were compared using functional pathways clustering and correlations to relevant clinical variables, genomic alterations, and microRNA regulation. We discovered that the dysregulation profiles of classical PTC (CPTC) and the tall cell variant (TCPTC) are similar and are distinct from that of the follicular variant (FVPTC). However, unique cancer or immune-associated genes are associated with clinical variables for each subtype. Cancer-related genes MUC1, FN1, and S100-family members were the most clinically relevant in CPTC, while APLN and IL16, both immune-related, were clinically relevant in FVPTC. RAET-family members, also immune-related, were clinically relevant in TCPTC. Collectively, our data suggest that dysregulation of both cancer and immune associated genes defines the gene expression landscapes of PTC variants, but different cancer or immune related genes may drive the phenotype of each variant.

SUBMITTER: Chakladar J

PROVIDER: S-EPMC6721495 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Papillary Thyroid Carcinoma Variants are Characterized by Co-dysregulation of Immune and Cancer Associated Genes.

Chakladar Jaideep J Li Wei Tse WT Bouvet Michael M Chang Eric Y EY Wang-Rodriguez Jessica J Ongkeko Weg M WM

Cancers 20190815 8

Papillary thyroid carcinoma (PTC) variants exhibit different prognosis, but critical characteristics of PTC variants that contribute to differences in pathogenesis are not well-known. This study aims to characterize dysregulated immune-associated and cancer-associated genes in three PTC subtypes to explore how the interplay between cancer and immune processes causes differential prognosis. RNA-sequencing data from The Cancer Genome Atlas (TCGA) were used to identify dysregulated genes in each va ...[more]

PMID: 31443155

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Project description:Background The genes and genetic mechanisms underlying the occurrence and progression of papillary thyroid carcinoma (PTC) are still unknown. This study aimed to find candidate genes related to the pathogenesis and progression of PTC. Methods RNA sequencing (RNA-seq) data of PTC and normal tissues were downloaded from The Cancer Genome Atlas (TCGA) database with clinical stage data to form a test, validation, and clinical-stage data matrix. We used the test data set to analyze differentially expressed genes (DEGs) and weighted gene co-expression network analysis (WGCNA) to find those gene clusters highly correlated with PTC. We then verified the expression of genes in the interested modules using the validation matrix. The quantitative real-time polymerase chain reaction (qRT-PCR) was used to verify the reliability of the expression of selected genes. Five key genes (GDF15, LCN2, KCNN4, SH3BGRL3, and MMP2) were used to analyze the connection between gene expression and the American Joint Committee on Cancer (AJCC) stage. The upregulated and downregulated DEGs, along with the modules of interest, were subjected to Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment using the Database for Annotation, Visualization, and Integrated Discovery (DAVID). Results We used WGCNA to find two modules of interest, the yellow module, which was positively associated with PTC, and the blue module, which was negatively correlated with PTC. Four genes (GDF15, LCN2, KCNN4, and SH3BGRL3) from the yellow module were determined to be highly expressed in PTC in the test data matrix and were verified in both the validation data matrix and quantitative real-time PCR, which indicated that these four genes were highly correlated with the occurrence of the PTC. Furthermore, these four genes also had a significantly higher expression in the advanced levels of pathological T, N, and AJCC stage, meaning that they were correlated with the progression of PTC. Genes in the yellow module and upregulated DEGs were significantly enriched in three vital signaling pathways, including focal adhesion, extracellular matrix (ECM)-receptor interaction, and the PI3K-Akt signaling pathway. Conclusions Four candidate genes (GDF15, LCN2, KCNN4, and SH3BGRL3) may be potential biomarkers for the PTC’s pathogenesis and may be useful for predicting the disease stage.

Project description:A high prevalence of thyroid papillary cancer was reported in hepatitis-C-virus (HCV) positive patients. However, the mechanistic role of hepatic-fibrosis in thyroid malignancy progressions is still unclear.We aimed to study the immune-modulatory interactions between thyroid papillary carcinoma and hepatic-fibrosis.Hepatic-fibrosis was induced in nude-nu-male mice by intra-peritoneal administration of carbon-tetrachloride. To induce thyroid-tumor, a thyroid papillary carcinoma cell line (NPA) was injected subcutaneously in the backs. Fibrotic profile was estimated by α-smooth-muscle-actin (αSMA) expression in liver tissue extracts using western-blots and RT-PCR. Intra-hepatic NK cells were isolated and stained for NK activity (CD107a) by flow cytometry. Liver histopathology (H&E staining), thyroid tumor mass and serum alanine aminotransferase (ALT), serum vascular endothelial growth factor (VEGF) and free-T4 levels were also assessed.Ex-vivo: NPA cells were co-cultured with intra-hepatic NK cells isolated from fibrotic mice with/without the tumor were analyzed for CFSE-proliferations. Both tumor groups (with/without hepatic-fibrosis) excreted higher serum free T4 levels. Hepatic-fibrosis increased tumor weight and size and serum free-T4 levels. In addition, tumor induction increased liver injury (both hepatic-fibrosis, necro-inflammation and serum ALT levels). In addition, tumor-bearing animals with hepatic-fibrosis had increased NK activity. NPA tumor-bearing animals increased fibrosis in spite of increased NK activity; probably due to a direct effect through increased serum free-T4 excretions. Serum VEGF levels were significantly increased in the fibrotic- bearing tumor groups compared to the non-fibrotic groups. In-vitro, NK cells from fibrotic tumor-bearing animals reduced proliferation of NPA cells. This decrease is attributed to increase NK cells activity in the fibrotic animals with the NPA tumors.Our results propose that NK cells although were stimulated in advanced fibrosis with tumor, they lost their anti-tumor and anti-fibrotic activity probably due to secretions of T4 and VEFG and may explain increased risk of thyroid tumors in chronic HCV patients.

Project description:BackgroundPapillary thyroid cancer has been associated with chronic inflammation. A systematic understanding of immune cell infiltration in PTC is essential for subsequent immune research and new diagnostic and therapeutic strategies.MethodsThree different algorithms, single-sample gene set enrichment analysis (ssGSEA), immune cell marker and CIBERSORT, were used to evaluate immune cell infiltration levels (abundance and proportion) in 10 data sets (The Cancer Genome Atlas [TCGA], GSE3467, GSE3678, GSE5364, GSE27155, GSE33630, GSE50901, GSE53157, GSE58545, and GSE60542; a total of 799 PTC and 194 normal thyroid samples). Consensus unsupervised clustering divided PTC patients into low-immunity and high-immunity groups. Weighted gene coexpression network analysis (WGCNA) and gene set enrichment analysis (GSEA) were used to analyze the potential mechanisms causing differences in the immune response.ResultsCompared with normal tissues, PTC tissues had a higher overall immune level and higher abundance levels and proportions of M2 macrophages, Tregs, monocytes, neutrophils, dendritic cells (DCs), mast cells (MCs), and M0 macrophages. Compared with early PTC, advanced PTC showed higher immune infiltration and higher abundance levels and proportions of M2 macrophages, Tregs, monocytes, neutrophils, DCs, MCs, and M0 macrophages. Compared to the low-immunity group, the high-immunity group exhibited more advanced stages, larger tumor sizes, greater lymph node metastases, higher tall-cell PTCs, lower follicular PTC proportions, more BRAF mutations, and fewer RAS mutations. Epstein-Barr virus (EBV) infection was the most significantly enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway for key module genes.ConclusionsIn human PTC, M2 macrophages, Tregs, monocytes, neutrophils, DCs, MCs, and M0 macrophages appear to play a tumor-promoting role, while M1 macrophages, CD8+ T cells, B cells, NK cells, and T follicular helper (TFH) cells (including eosinophils, γδ T cells, and Th17 cells with weak supporting evidence) appear to play an antitumor role. During the occurrence and development of PTC, the overall immune level was increased, and the abundance and proportion of tumor-promoting immune cells were significantly increased, indicating that immune escape had been aggravated. Finally, we speculate that EBV may play an important role in changing the immune microenvironment of PTC tumors.

Dataset Information

Papillary Thyroid Carcinoma Variants are Characterized by Co-dysregulation of Immune and Cancer Associated Genes.

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Papillary Thyroid Carcinoma Variants are Characterized by Co-dysregulation of Immune and Cancer Associated Genes.

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