Clinical prognostic significance of cancer stem cell markers in patients with papillary thyroid carcinoma.
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ABSTRACT:
SUBMITTER: Ryu YJ
PROVIDER: S-EPMC6924097 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Secreted Protein Acidic and Rich in Cysteine (SPARC)-related modular calcium-binding protein-2 (SMOC2), a secreted matricellular protein, is reported to be involved in various processes related to cancer progression such as regulating the cell cycle, angiogenesis, and invasion. However, its expression and prognostic significance in papillary thyroid carcinomas (PTCs) remains unknown. Using immunohistochemistry, we evaluated the expression profile of SMOC2 and its prognostic value in a large cohort of PTCs. Real time-PCR analysis with fresh-frozen tissues showed that SMOC2 mRNA expression in PTCs was substantially lower than the expression in matched non-cancerous thyroid tissues, consistent with the results from thyroid cancer cell lines. Immunohistochemical analysis demonstrated that SMOC2 was normally present in thyroid follicular epithelial cells and the expression level was maintained in nodular hyperplasia. However, SMOC2 expression was significantly lower in lymphocytic thyroiditis and follicular tumors including follicular adenomas and carcinomas. In particular, 38% of PTCs exhibited a complete loss of SMOC2 expression, which was associated with the presence of BRAF (V600E) mutation. Moreover, SMOC2 further declined during lymph node metastasis in PTCs. DNA methylation chip analysis revealed one hypermethylated CpG site in the promoter region of SMOC2 gene, suggesting an epigenetic regulation of SMOC2 in PTCs. Remarkably SMOC2 positivity was associated with improved recurrence-free survival along with female sex, tumor size, and the N stage. However, SMOC2 was not identified as an independent prognostic marker in multivariate analyses. Taken together, SMOC2 expression is significantly down-regulated in PTCs and SMOC2 positivity is closely associated with better clinical outcomes, suggesting that SMOC2 can be a prognostic marker in PTC patients.
| S-EPMC7078233 | biostudies-literature
Project description:This study screened microRNAs (miRNAs) that are abnormally expressed in papillary thyroid carcinoma (PTC) tissues to identify PTC and nodular goiter and the degree of PTC malignancy. A total of 51 thyroid tumor tissue specimens paired with adjacent normal thyroid tissues were obtained from the Department of Surgical Oncology of Hangzhou First People's Hospital from June-December 2011. miRNA expression profiles were examined by microarrays and validated by quantitative real-time PCR (qRT-PCR). Expression levels of the miRNAs were analyzed to assess if they were associated with selected clinicopathological features. Eleven miRNAs were significantly differentially expressed between nodular goiter and PTC and between highly invasive and low invasive PTC. miR-199b-5p and miR-30a-3p were significantly differentially expressed among the three groups. miR-30a-3p, miR-122-5p, miR-136-5p, miR-146b-5p and miR-199b-5p were selected for further study by qRT-PCR and miR-146b-5p, miR-199b-5p and miR-30a-3p were different between the PTC and nodular goiter groups. miR-199b-5p was over-expressed in PTC patients with extrathyroidal invasion and cervical lymph node metastasis. In conclusion miR-146b-5p, miR-30a-3p, and miR-199b-5p may serve as biomarkers for the diagnosis of PTC and miR-199b-5p is associated with PTC invasiveness.
| S-EPMC6271659 | biostudies-literature
Project description:IntroductionThe cancer stem cell (CSC) hypothesis states that tumours consist of a cellular hierarchy with CSCs at the apex driving tumour recurrence and metastasis. Hence, CSCs are potentially of profound clinical importance. We set out to establish the clinical relevance of breast CSC markers by profiling a large cohort of breast tumours in tissue microarrays (TMAs) using immunohistochemistry (IHC).MethodsWe included 4, 125 patients enrolled in the SEARCH population-based study with tumours represented in TMAs and classified into molecular subtype according to a validated IHC-based five-marker scheme. IHC was used to detect CD44/CD24, ALDH1A1, aldehyde dehydrogenase family 1 member A3 (ALDH1A3) and integrin alpha-6 (ITGA6). A 'Total CSC' score representing expression of all four CSC markers was also investigated. Association with breast cancer specific survival (BCSS) at 10 years was assessed using a Cox proportional-hazards model. This study was complied with REMARK criteria.ResultsIn ER negative cases, multivariate analysis showed that ITGA6 was an independent prognostic factor with a time-dependent effect restricted to the first two years of follow-up (hazard ratio (HR) for 0 to 2 years follow-up, 2.4; 95% confidence interval (95% CI), 1.2 to 4.8; P = 0.009). The composite 'Total CSC' score carried independent prognostic significance in ER negative cases for the first four years of follow-up (HR for 0 to 4 years follow-up, 1.3; 95% CI, 1.1 to 1.6; P = 0.006).ConclusionsBreast CSC markers do not identify identical subpopulations in primary tumours. Both ITGA6 and a composite Total CSC score show independent prognostic significance in ER negative disease. The use of multiple markers to identify tumours enriched for CSCs has the greatest prognostic value. In the absence of more specific markers, we propose that the effective translation of the CSC hypothesis into patient benefit will necessitate the use of a panel of markers to robustly identify tumours enriched for CSCs.
| S-EPMC3326560 | biostudies-literature
Project description:The prognostic role of molecular markers in papillary thyroid carcinoma (PTC) is a matter of ongoing debate. The aim of our study is to investigate the impact of RAS, BRAF, TERT promoter mutations and RET/PTC rearrangements on the prognosis of PTC patients. We performed a search in four electronic databases: PubMed, Scopus, Web of Science and Virtual Health Library (VHL). Data of hazard ratio (HR) and its 95% confidence interval (CI) for disease-specific survival (DSS) and disease-free survival (DFS) were directly obtained from original papers or indirectly estimated from Kaplan-Meier curve (KMC). Pooled HRs were calculated using random-effect model weighted by inverse variance method. Publication bias was assessed by using Egger's regression test and visual inspection of funnel plots. From 2630 studies, we finally included 35 studies with 17,732 patients for meta-analyses. TERT promoter mutation was significantly associated with unfavorable DSS (HR = 7.64; 95% CI = 4.00-14.61) and DFS (HR = 2.98; 95% CI = 2.27-3.92). BRAF mutations significantly increased the risk for recurrence (HR = 1.63; 95% CI = 1.27-2.10) but not for cancer mortality (HR = 1.41; 95% CI = 0.90-2.23). In subgroup analyses, BRAF mutation only showed its prognostic value in short-/medium-term follow-up. Data regarding RAS mutations and RET/PTC fusions were insufficient for meta-analyses. TERT promoter mutation can be used as an independent and reliable marker for risk stratification and predicting patient's outcomes. The use of BRAF mutation to assess patient prognosis should be carefully considered.
| S-EPMC5424840 | biostudies-literature
Project description:BackgroundPapillary thyroid cancer (PTC) is reported to be highly heritable in epidemiological studies. Genome-wide association studies (GWAS) have uncovered several variants associated with PTC predisposition. It remains unknown whether these variants might contribute to better clinical stratification of PTC patients.MethodsIn order to assess the usefulness of germline genetic analyses in the management of PTC patients, the genotypes of five variants (rs965513, rs944289, rs116909374, rs2439302, and rs966423) were determined in 1216 PTC patients and 1416 controls. Additionally, the expression of seven genes located close to GWAS variants (PTCSC3, MBIP, NKX2-1, FOXE1, DIRC3, PTCSC2, and NRG1) were measured in 73 PTC paired tumor/normal tissues, respectively. Next, the association was analyzed between the genotypes of the germline variants and the levels of gene expression with clinical/pathological features such as age, sex, TNM staging, multifocality status, extrathyroidal expansion, and MACIS score.ResultsThe risk allele of rs965513 was associated with larger tumor size (p = 0.025) and extrathyroidal expansion (odd ratio [OR] = 1.29, p = 0.045). The variant rs2439302 showed association with lymph node metastasis (OR = 1.24, p = 0.016), and multifocality status of the tumor (OR = 1.24, p = 0.012). The expression of MBIP was associated with T stage (p = 0.010). MBIP and PTCSC3 displayed lower expression in PTC tissue in males than in females (p = 0.025 and p = 0.036, respectively). NKX2-1 displayed lower expression in patients with N1 stage (p = 0.040).ConclusionsThe studied germline risk alleles predisposing to PTC were associated with a more aggressive course of the disease reflected by larger tumor diameter, higher multifocality rate, and more advanced N stage at the time of diagnosis. These results show that germline variants not only predispose to PTC but also might impact its clinical course. However, these associations were only moderate, and further large multi-ethnic studies are required to evaluate the usefulness of these germline variants in the clinical stratification of PTC patients.
| S-EPMC5036310 | biostudies-literature
Project description:Objectives:Many patients with papillary thyroid cancer (PTC) have a high recurrence risk and poor prognosis, and the main obstacle to the clinical diagnosis and treatment of PTC is lack of effective predictive molecular markers. The purpose of this study was to investigate the clinicopathological and prognostic implications of WW domain binding protein 5 (WBP5) expression in PTC. Materials and Methods:Immunohistochemistry of WBP5 was performed using tissue microarrays of 131 patients with PTC who underwent surgery during January 2006 and January 2010 in the Zhejiang Cancer Hospital. Statistical analyses were conducted to evaluate the association between WBP5 expression and the clinicopathological features and to analyze the disease-free survival (DFS) and prognostic factors. Results and Conclusion:The positive expression rate of WBP5 in PTC and the adjacent normal tissues was 42.75% (56/131) and 45.45% (10/22), respectively. WBP5 expression was significantly correlated with bilaterality, capsule invasion, and N-stage, and it was a favorable factor of DFS. Moreover, patients with a high WBP5 expression exhibited reduced risk of disease recurrence compared with that in patients with low WBP5 expression in the univariate analysis, whereas the multivariate analysis suggested that WBP5 was not an independent prognostic factor. Our results indicate that WBP5 might be a favorable prognosis indicator of PTC.
| S-EPMC6885795 | biostudies-literature
Project description:Objective: Mitochondrial NADP+-dependent isocitrate dehydrogenase 2 (IDH2) is a major producer of mitochondrial NADPH. IDH2-related research has focused on its mutation mechanism and its clinical significance, but the role of wild-type IDH2 in carcinoma remains controversial. Altered IDH2 levels have been identified in several types of carcinomas. However, the significance and expression of IDH2 in thyroid cancer remains unknown. Methods: We examined the expression of IDH2 in thyroid cancer and adjacent normal tissues using quantitative real-time PCR (qRT-PCR), immunohistochemical (IHC) staining analyses, and western blot analysis with frozen tissues. The relationship between IDH2 and the clinicopathological features of thyroid cancer was analyzed by IHC. Subsequently, we investigated the function of wild-type IDH2 in thyroid cancer cells in vitro. Results: We found that the mRNA expression and protein levels of IDH2 were higher in tumor than in adjacent tissues, when evaluated by qRT-PCR, western blot, and IHC analyses. Tumor size, T stage, lymph node metastasis, and TNM stage showed significant differences between the IDH2 high expression and low expression groups. Multiple logistic regression analyses indicated that tumor size and IDH2 expression were significantly correlated with the occurrence of neck LNM. Furthermore, CCK8 levels, colony formation, and invasive cell number were decreased in the sh-IDH2 groups. The upregulation of IDH2 in thyroid cancer cells showed opposite effects. Conclusion: Our results indicated that IDH2 may play an important role in the development of thyroid cancer. IDH2 can be used as a potential biomarker for diagnosis and prognosis and may be a potential therapeutic target for thyroid cancer.
| S-EPMC6503344 | biostudies-literature
Project description:Background: B7-H3, also known as CD276, an important immune checkpoint member of the B7-CD28 family, is confirmed as a promising target after PD-L1 in clinical trials. Although the overexpression of B7-H3 has been associated with invasive metastatic potential and poor prognosis in multiple types of cancer, nothing is known regarding the expression profiles of B7-H3 in papillary thyroid carcinoma (PTC). In this study, we carried out a large-scale analysis of B7-H3 expression in PTC patients and evaluated the potential clinical significance of B7-H3. Methods: In total, data from 1,210 samples, including 867 cases from TCGA and four GEO datasets, were collected for B7-H3-related transcriptome analyses, and 343 postoperative, whole-tumor sections were collected from patients with PTC at our institute for B7-H3-specific immunohistochemistry (IHC) staining. The statistical analysis was primarily accomplished using the R project for statistical computing. Results: B7-H3 positivity was found in 84.8% of PTC patients (291/343), and the mRNA and protein expression levels of B7-H3 in PTC were markedly higher than those of para-tumor tissues (p < 0.001), demonstrating that B7-H3 can serve as a potential diagnostic biomarker for PTC. The significant upregulation of B7-H3 in PTC is caused by distinct patterns of CNVs and CpG DNA methylation. Functional enrichment analysis confirmed that high B7-H3 expression was significantly associated with specific immune features and angiogenesis. High B7-H3 protein expression was associated with tumor size (p = 0.022), extrathyroidal extension (ETE) (p = 0.003), and lymph node metastasis (LNM) (p < 0.001). More importantly, multivariate analysis confirmed that B7-H3 was an independent predictor of relapse-free survival (RFS) (p < 0.05). In the subgroup analysis, positive B7-H3 staining was associated with worse RFS in patients with primary tumor size ≥2 cm (p < 0.05), age ≥55 years (p < 0.05), LNM (p = 0.07), multifocality (p < 0.05), and ETE (p < 0.05). In addition, Circos plots indicated that B7-H3 was significantly associated with other immune checkpoints in the B7-CD28 family. Conclusion: This is the first comprehensive study to elucidate the expression profile of B7-H3 in PTC. Our observations revealed that B7-H3 is a novel independent biomarker for predicting LNM and disease recurrence for PTC patients, and it thus may serve as an indicator that could be used to improve risk-adapted therapeutic strategies and a novel target for immunotherapy strategies for patients who undergo an aggressive disease course.
| S-EPMC9039293 | biostudies-literature
Project description:Fine needle aspiration biopsy (FNAB) is a standard procedure for the detection of thyroid nodules malignancy, yet 10-25% of the sample diagnosed may go undetermined or suspicious. The utility of cancer stem cell markers (CSCM) as a differential diagnosis molecular marker in nodules of suspicious decision in FNAB was hypothesized. Papillary thyroid carcinoma (PTC) and thyroid fibroadenoma (TFA) samples were selected to test the hypothesis. The samples employed in this study were from patients who had thyroid hyperplasia and a suspicious or undetermined diagnosis by FNAB. The patient underwent a successful thyroidectomy at Al-Yarmouk Teaching Hospital in Baghdad between January 2015 and December 2017. All nodule samples underwent a systematic histopathological examination after resection. Tumors diagnosed as PTC and those diagnosed as fibroadenoma (TFA) were selected for this study. Collectively 39 PTC and 11 TFA nodules were included. Quantitative reverse transcriptase real-time PCR (qRT-PCR) and immunohistochemistry (IHC) were used to determine levels of mRNA and proteins of CSCM ALDH1A1, CD44, ABCG2, and Oct3/4 in both types of tumors were used. This study revealed that the expression levels of CSCM were significantly increased in PTC tissues when compared to benign tissues and the positive correlation was found between the CSCM expression levels and tumor stage, size, and gender. In conclusion, for a more precise diagnosis, we suggest these markers be included in what is currently available to characterize malignancy from what is not in thyroid cancer, as well as for the staging process of PTC.
| S-EPMC6613036 | biostudies-literature
Project description:Background:The primary goal of papillary thyroid cancer (PTC) management was to stratify patients at pre- and post-surgical level to identify the small proportion of cases with potentially aggressive disease. Purpose:The aim of our study is to evaluate the possible role of programmed cell death 4 (PDCD4) and BRAF status as prognostic markers in PTC. Patients and methods:We investigate programmed cell death 4 (PDCD4) immunohistochemical expression in 125 consecutive PTCs with median follow-up of 75.3 months (range, 15-98 months) to verify the possible correlation between BRAF status and correlate the classical clinicopathological prognostic factors and PTC outcome with PDCD4 expression. To further support the data, miR-21 expression was tested (by quantitative real-time PCR and in situ hybridization) in a different series of 30 cases (15 PTCs BRAFwt and 15 PTCs BRAFV600E). Moreover, we validated our results using TGCA thyroid carcinoma dataset. Results:We found that 59.8% of the patients showed low-grade PDCD4 nuclear expression and low-grade expression correlated with BRAF V600E. Compared with BRAF 15 wild-type tissue samples, a significant miR-21 up-regulation was associated with BRAF V600E mutations. Low-grade PDCD4 resulted, and was associated with aggressive histological variants, higher cancer size, extra-thyroidal extension, multifocality, lymph-node metastasis and lymph nodal ratio at the diagnosis. Concerning the outcome, the low-grade PDCD4 expression correlated at univariate and multivariate analysis, with lower levels of recurrence-free survival rate (RFS) and with poor outcome. Moreover, there was significant association between BRAF V600E patients with PDCD4 nuclear loss and lower RFS, whilet here was significant association between BRAF wild-type patients with PDCD4 nuclear expression and better outcome. Conclusion:These results showed that PDCD4 could predict PTC outcome and that the sum of PDCD4 and BRAF alterations increases the prognostic power of BRAF mutation alone.
| S-EPMC6708393 | biostudies-literature