Thyroid Carcinoma Susceptibility Research Articles

Human bone marrow mesenchymal stem cell-driven LncRNA PTCSC3 upregulation within lung adenocarcinoma cells reduces erlotinib resistance by mitigating Wnt/β-Catenin pathway.

lncRNA PTCSC3, which stands for Papillary Thyroid Carcinoma Susceptibility Candidate 3, has been found to play a role in various cellular processes, including cell proliferation, apoptosis, and migration, acting as either an oncogene or a tumor suppressor depending on the context. This study investigates the influence of lncRNA PTCSC3, derived from human bone marrow mesenchymal stem cell (hBMSC), on the efficacy of erlotinib (Er)-resistant lung adenocarcinoma (LUAD) cells and elucidates underlying mechanism. The hBMSCs and LUAD (PC9 and A549) cells were employed to establish an Er-resistant LUAD cell model. It was observed that exposure to hBMSCs reduced the viability of A549-Er and PC9-Er cells and increased their rate of apoptosis. Further investigations revealed that in the presence of hBMSCs-containing medium, PTCSC3 expression was significantly upregulated, concomitantly with a suppression of the Wnt/β-Catenin pathway. Conversely, silencing PTCSC3 led to enhanced A549-Er and PC9-Er activities, reduced cell apoptosis, and activated Wnt/β-Catenin pathway. The effects of PTCSC3 modulation were also examined by transfecting LUAD cells with different PTCSC3 expression vectors and treating them with XAV939, a Wnt/β-Catenin pathway inhibitor, which similarly decreased cell viability. In the rescue experiment, the effect of hBMSCs on LUAD cells could be counteracted by down-regulation of PTCSC3, and the effect of PTCSC3 down-regulation on cells was mitigated by XAV939. This study revealed that hBMSCs promote the up-regulation of PTCSC3 in LUAD cells, thus inhibiting Wnt/β-Catenin pathway and reversing Er resistance, offering a potential novel strategy to enhance the efficacy of chemotherapy in LUAD.

Variants in TPO rs2048722, PTCSC2 rs925489 and SEMA4G rs4919510 affect thyroid carcinoma susceptibility risk

BackgroundThyroid carcinoma (THCA) is a malignant endocrine tumor all around the world, which is influenced by genetic and environmental factors.ObjectiveTo explore the association between TPO rs2048722, PTCSC2 rs925489, SEMA4G rs4919510 polymorphisms and THCA susceptibility in Chinese population.MethodsWe recruited 365 THCA patients and 498 normal controls for the study. Logistic regression analysis was used to evaluate the association between TPO rs2048722, PTCSC2 rs925489, SEMA4G rs4919510 polymorphisms and THCA susceptibility. MDR was used to assess the genetic interactions among the three SNPs.ResultsOverall analysis demonstrated that rs925489 of PTCSC2 was evidently associated with increased risk of THCA in multiple genetic models (OR = 1.59, 95%CI = 1.12–2.24, p = 0.009). The results of stratified analysis illustrated that rs2048722 of TPO can significantly increase the THCA susceptibility of participants less than or equal to 44 years old and smokers. Similarly, rs925489 of PTCSC2 obviously improved the risk of THCA among participants older than 44 years, males, smokers and drinkers. However, rs4919510 of SEMA4G has a protective effect on the development of THCA among participants with less than or equal to 44 years old and non-drinkers. Interestingly, there was a strong genetic interaction among the three SNPs in the occurrence of THCA risk.ConclusionTPO rs2048722, PTCSC2 rs925489 and SEMA4G rs4919510 polymorphisms were evidently associated with the risk of THCA in the Chinese population, which was affected by age, gender, smoking and drinking consumption.

Suggestive evidence of the genetic association of TMOD1 and PTCSC2 polymorphisms with thyroid carcinoma in the Chinese Han population

BackgroundThe purpose of this study was to survey the associations of six single nucleotide polymorphisms (SNPs) in the TMOD1 and PTCSC2 genes with thyroid carcinoma (TC).MethodPeripheral blood samples were obtained from 510 patients with TC and 509 normal controls. Six SNPs were genotyped by the Agena MassARRAY platform. Logistic regression was used to evaluate the association between SNPs and TC susceptibility by calculating odds ratios (ORs) and 95% confidence intervals (CIs). SNP-SNP interactions were analyzed by multifactor dimensionality reduction (MDR).ResultsOur study showed that rs925489 (OR = 1.45, p = 0.011) and rs965513 (OR = 1.40, p = 0.021) were significantly associated with an increased risk of TC. Rs10982622 decreased TC risk (OR = 0.74, p = 0.025). Further stratification analysis showed that rs10982622 reduced the susceptibility to TC in patients aged ≤ 45 years (OR = 0.69, p = 0.019) and in females (OR = 0.61, p = 0.014). Rs925489 increased TC risk in people aged > 45 years (OR = 1.54, p = 0.044) and in males (OR = 2.34, p = 0.003). In addition, rs965513 was related to an increased risk of TC in males (OR = 2.14, p = 0.007). Additionally, haplotypes in the block (rs925489|rs965513) significantly increased TC risk (p < 0.05). The best predictive model for TC was the combination of rs1052270, rs10982622, rs1475545, rs16924016, and rs925489.ConclusionTMOD1 and PTCSC2 polymorphisms were separately correlated with a remarkable decrease and increase in TC risk based on the analysis.

Genetic signature of differentiated thyroid carcinoma susceptibility: a machine learning approach.

To identify a peculiar genetic combination predisposing to differentiated thyroid carcinoma (DTC), we selected a set of single nucleotide polymorphisms (SNPs) associated with DTC risk, considering polygenic risk score (PRS), Bayesian statistics and a machine learning (ML) classifier to describe cases and controls in three different datasets. Dataset 1 (649 DTC, 431 controls) has been previously genotyped in a genome-wide association study (GWAS) on Italian DTC. Dataset 2 (234 DTC, 101 controls) and dataset 3 (404 DTC, 392 controls) were genotyped. Associations of 171 SNPs reported to predispose to DTC in candidate studies were extracted from the GWAS of dataset 1, followed by replication of SNPs associated with DTC risk (P < 0.05) in dataset 2. The reliability of the identified SNPs was confirmed by PRS and Bayesian statistics after merging the three datasets. SNPs were used to describe the case/control state of individuals by ML classifier. Starting from 171 SNPs associated with DTC, 15 were positive in both datasets 1 and 2. Using these markers, PRS revealed that individuals in the fifth quintile had a seven-fold increased risk of DTC than those in the first. Bayesian inference confirmed that the selected 15 SNPs differentiate cases from controls. Results were corroborated by ML, finding a maximum AUC of about 0.7. A restricted selection of only 15 DTC-associated SNPs is able to describe the inner genetic structure of Italian individuals, and ML allows a fair prediction of case or control status based solely on the individual genetic background.

Fine-mapping of two differentiated thyroid carcinoma susceptibility loci at 2q35 and 8p12 in Europeans, Melanesians and Polynesians.

Differentiated thyroid carcinoma (DTC) incidence is characterized by wide ethnic and geographic variations, with high incidence rates observed in Oceanian populations. Genome-wide association studies (GWAS) identified mainly four DTC susceptibility loci at 9q22.33, 14q13.3, 2q35 and 8p12. Here we performed fine-mapping of the 2q35 and 8p12 loci in the population of the EPITHYR consortium that includes Europeans, Melanesians and Polynesians to identify likely causal variants for DTC risk. We conducted a colocalization analysis using eQTLs data to determine the SNPs with the highest probability of causality.At 2q35, we highlighted rs16857609 located in DIRC3. This SNP has a high probability of causality in the three populations, and a significant association in Europeans (OR = 1.4, p = 1.9 x 10-10). It is also associated with expression of DIRC3 and of the nearby gene IGFBP5 in thyroid tumour cells. At 8p12, we identified rs7844425 which was significantly associated with DTC in Europeans (OR = 1.32, p = 7.6 x 10-8) and rs2439304, which was highlighted by the colocalization analysis but only moderately associated with DTC in our dataset (OR = 1.2, p = 0.001). These SNPs are linked to the expression of NRG1 in thyroid tissue.Hence, our study identified novel variants at 2q35 and 8p12 to be prioritized for further functional studies.

The effects of the genetic polymorphisms of antioxidant enzymes on susceptibility to papillary thyroid carcinoma.

Several lines of evidences have indicated that inflammation play an important role in the carcinogenesis. During the inflammatory processes, free radical species are produced from oxidative stress. In normal conditions, enzymatic and nonenzymatic antioxidants remove these products. Manganese superoxide dismutase (MnSOD), glutathione peroxidase-1 (GPx-1), and catalase (CAT) are three important enzymes. Therefore, this study aimed to evaluate the effects of MnSOD (SOD2), GPX-1, and CAT genetic polymorphisms on papillary thyroid carcinoma (PTC) susceptibility. A total of 134 patients with PTC and 151 healthy controls were recruited to participate in this study. All samples were genotyped for SOD2 rs4880, GPX1 1050450, and CAT rs7943316 polymorphisms by polymerase chain reaction-restriction fragment length polymorphism method. The frequencies of the rs1050450, rs4880, and rs7943316 alleles and genotypes were not different between PTC patients and controls. However, the TC genotype of SOD2 rs4880 polymorphism was significantly higher in males compared to that in females in PTC patients (odds ratio [OR], 3.9 [95% CI, 1.5-11], p = .007). The rs4880 polymorphism was also associated with higher stages (III-IV) of PTC in dominant model. No significant correlation was found between GPX1-rs1050450 and CAT-rs7943316 polymorphisms and demographic, clinical, and pathological features of the disease. The SOD2 rs4880CT genotype was more frequent in males with PTC and patients with higher stages (III-IV) of disease (OR, 2.9 [95% CI, 1.1-7.7], p = .04). However, no significant association was found between GPX1-rs1050450 and CAT-rs7943316 variants and PTC or its demographic, clinical, and pathological features.

The effect of TP53 and P21 gene polymorphisms on papillary thyroid carcinoma susceptibility and clinical/pathological features.

Papillary thyroid cancer (PTC) is the most common thyroid malignancy. Genetic polymorphisms of the TP53 and P21 genes are the candidate variants in various cancers development. This study investigated whether the polymorphisms in TP53 (rs1042522) and P21 (rs1059234 and rs1801270) affect the risk of PTC and whether such the genotype of these polymorphisms is associated with pathological and clinical characteristics of PTC. A case-control study was conducted with 286 Iranian people, including 131 PTC cases and 155 healthy controls. The genetic polymorphisms were investigated by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Our results suggested that TP53-rs1042522 CC genotype was significantly associated with protection against PTC, in the dominant, recessive and allelic models (OR = 0.4, 95%CI: 0.2-0.8, P = .008; OR = 0.5, 95%CI: 0.3-0.9, P = .01; OR = 0.6, 95%CI: 0.4-0.8, P = .002, respectively). The rs1042522 was associated with PTC patients with tumor size greater than 1 cm in dominant and recessive models (OR = 0.2, 95%CI = 0.04-0.9, P = .04 and OR = 0.3, 95%CI = 0.1-0.7, P = .009, respectively) and was associated with vascular invasion in dominant model (OR = 0.3, 95%CI = 0.1-0.7, P = .01). No correlation was identified between P21 rs1059234 and rs1801270 polymorphisms and risk of PTC and pathological and clinical characteristics of PTC. Genetic variations in rs1042522 might alter the PTC risk, which could affect tumor size and cause lower incidence of vascular invasion in PTC cases. This was the first report suggesting that no correlation was found between P21 rs1059234 and rs1801270 polymorphisms and PTC risk. Thus, more studies with a larger population size and different ethnic groups and functional assays are needed to confirm our results.

LncRNA PTCSC3 inhibits the proliferation, invasion and migration of cervical cancer cells via sponging miR-574-5p.

Dysregulation of long non-coding RNA papillary thyroid carcinoma susceptibility candidate 3 (lncRNA PTCSC3) has been found to correlate with various types of cancers. Quantitative RT-PCR showed a down-regulation of PTCSC3 in cervical cancer tissues compared with normal cervical tissues. The present study aimed to investigate the role of lncRNA PTCSC3 in cervical cancer and the underlying mechanisms. PTCSC3 was overexpressed in cervical cancer cell lines C-33A and Hela by transfection with pcDNA3.1-lncRNA PTCSC3 expressing plasmid. Overexpression of lncRNA PTCSC3 inhibited cell proliferation, induced cell cycle arrest, and suppressed cell invasion and migration using CCK8 assay, flow cytometry, Transwell assay and wound healing examination, respectively. Western blotting analysis showed that PTCSC3 overexpression decreased the expression of cyclinD1, matrix metalloproteinases 9 (MMP9), N-cadherin and β-catenin and increased E-cadherin expression. Further, PTCSC3 negatively regulated miR-574-5p expression and dual-luciferase assay verified the binding activity between miR-574-5p and lncRNA PTCSC3. Enforced up-regulation of miR-574-5p abolished the inhibitory effect of lncRNA PTCSC3 on cervical cancer cell proliferation, invasiveness and mobility. Taken together, lncRNA PTCSC3 inhibited cell growth and metastasis via sponging miR-574-5p in cervical cancer. Therefore, we demonstrate the tumour-suppressive function of lncRNA PTCSC3 in cervical cancer and suggest that PTCSC3 is a potential therapeutic target for cervical cancer.

LncRNA PTCSC3 Is a Biomarker for the Treatment and Prognosis of Gastric Cancer.

Background: Long noncoding RNA (lncRNA) papillary thyroid carcinoma susceptibility candidate 3 (PTCSC3) inhibits several types of cancer, whereas its role in gastric cancer is unknown. Materials and Methods: From May 2010 to May 2015, this study included 68 (36 males and 32 females, 35-69 years, 48.3 ± 7.1 years) gastric cancer patients and 60 healthy volunteers (32 males and 28 females, 34-67 years, 48.8 ± 6.5 years). Transient transfections, QPCR, CCK-8, transwell cell migration, and invasion assay were used for carrying out the research. Results: The authors found that plasma PTCSC3 was downregulated in gastric cancer patients. Downregulation of PTCSC3 distinguished early stage gastric cancer patients from healthy controls. LncRNA PTCSC3 expression levels were increased on the day of discharge in gastric cancer patients compared with pretreatment levels. During follow-up, patients with low plasma levels of PTCSC3 showed a significantly lower overall survival rate. PTCSC3 negatively regulated proliferation, invasion, and migration of gastric cancer cells. Conclusions: Therefore, lncRNA PTCSC3 may serve as a biomarker for the treatment and prognosis of gastric cancer.

LncRNA papillary thyroid carcinoma susceptibility candidate 3 (PTCSC3) regulates the proliferation of human periodontal ligament stem cells and toll-like receptor 4 (TLR4) expression to improve periodontitis

BackgroundLncRNA PTCSC3 is a known tumor suppressor, while its roles in other human diseases are unclear.MethodsAll participants were admitted by The second Affiliated Hospital, School of Medicine, Zhejiang University from January 2016 to January 2018. RT-qPCR, Vectors, cell transfection, In vitro cell proliferation assay and western blot were using to carry out the experiment.ResultsIn this study we found that PTCSC3 was downregulated, while toll-like receptor 4 (TLR4) was upregulated in periodontal ligament stem cells (PDLSCs) isolated from periodontitis affected teeth that in PDLSCs isolated from healthy teeth. Expression levels of PTCSC3 and TLR4 were only significantly and inversely correlated in PDLSCs isolated from periodontitis affected teeth but not in PDLSCs isolated from healthy teeth. PTCSC3 overexpression led to the downregulation of TLR4 in PDLSCs isolated from periodontitis affected teeth, while TLR4 overexpression failed to significantly affect PTCSC3. PTCSC3 overexpression also led to the inhibited proliferation of periodontitis-affected PDLSCs.ConclusionsTherefore, lncRNA PTCSC3 may regulate the proliferation of PDLSCs and TLR4 expression to improve periodontitis.

The relationship between RASSF1A promoter methylation and thyroid carcinoma: A meta-analysis of 14 articles and a bioinformatics of 2 databases (PRISMA).

DNA promoter methylation can suppresses gene expression and shows an important role in the biological functions of Ras association domain family 1A (RASSF1A). Many studies have performed to elucidate the role of RASSF1A promoter methylation in thyroid carcinoma, while the results were conflicting and heterogeneous. Here, we analyzed the data of databases to determine the relationship between RASSF1A promoter methylation and thyroid carcinoma. We used the data from 14 cancer-normal studies and Gene Expression Omnibus (GEO) database to analyze RASSF1A promoter methylation in thyroid carcinoma susceptibility. The data from the Cancer Genome Atlas project (TCGA) database was used to analyze the relationship between RASSF1A promoter methylation and thyroid carcinoma susceptibility, clinical characteristics, prognosis. Odds ratios were estimated for thyroid carcinoma susceptibility and hazard ratios were estimated for thyroid carcinoma prognosis. The heterogeneity between studies of meta-analysis was explored using H, I values, and meta-regression. We adopted quality criteria to classify the studies of meta-analysis. Subgroup analyses were done for thyroid carcinoma susceptibility according to ethnicity, methods, and primers. Result of meta-analysis indicated that RASSF1A promoter methylation is associated with higher susceptibility to thyroid carcinoma with small heterogeneity. Similarly, the result from GEO database also showed that a significant association between RASSF1A gene promoter methylation and thyroid carcinoma susceptibility. For the results of TCGA database, we found that RASSF1A promoter methylation is associated with susceptibility and poor disease-free survival (DFS) of thyroid carcinoma. In addition, we also found a close association between RASSF1A promoter methylation and patient tumor stage and age, but not in patients of different genders. The methylation status of RASSF1A promoter is strongly associated with thyroid carcinoma susceptibility and DFS. The RASSF1A promoter methylation test can be applied in the clinical diagnosis of thyroid carcinoma.

LncRNA PTCSC3/miR-574-5p Governs Cell Proliferation and Migration of Papillary Thyroid Carcinoma via Wnt/β-Catenin Signaling.

The distance metastases of papillary thyroid carcinoma (PTC) were a major threaten for PTC patients, thus, to study the potential mechanism for the treatment of PTC was essential. Previous studies have shown that PTCSC3 (Thyroid Carcinoma Susceptibility Candidate 3), miR-574-5p and Wnt/β-catenin were involved in PTC, but the potential pathogenic mechanism among them was still unclear. Real-time PCR and Western blot were used to detect genes expression. Luciferase reporter assay was used to detect the combination of miR-574-5p and suppressor of cancer cell invasion (SCAI), as well as the ratio of TOP/FOP. RNA Pull-down assay verified the bound of PTCSC3 and miR-574-5p. MTT assay, Transwell assay, and wound scratch assay were used to detect cell viability and cell migration. The expression of PTCSC3 and SCAI were decreased, while miR-574-5p and β-catenin were increased in PTC tissues and cells. Overexpressed PTCSC3 suppressed cell proliferation and migration, promoted the expression of SCAI, but inhibited β-catenin. PTCSC3 absorbed miR-574-5p, and miR-574-5p targeted to SCAI; SCAI could regulate the activity of Wnt/β-catenin. PTCSC3/miR-574-5p regulated the activity of Wnt/β-catenin via SCAI and mediated cell proliferation and migration of PTC-1. In vivo experiments verified the fact that overexpressed PTCSC3 inhibited tumor growth. The signaling PTCSC3-miR-574-5p-SCAI-Wnt/β-catenin mediated the proliferation and migration of PTC-1 cells, which was vital for the further PTC therapy and prognosis. J. Cell. Biochem. 118: 4745-4752, 2017. © 2017 Wiley Periodicals, Inc.

Long noncoding RNA papillary thyroid carcinoma susceptibility candidate 3 (PTCSC3) inhibits proliferation and invasion of glioma cells by suppressing the Wnt/\u03b2-catenin signaling pathway

BackgroundThe dysregulation of long noncoding RNAs (lncRNAs) has been identified in a variety of cancers. An increasing number of studies have found the critical role of lncRNAs in the regulation of cellular processes, such as proliferation, invasion and differentiation. Long noncoding RNA papillary thyroid carcinoma susceptibility candidate 3 (PTCSC3) is a novel lncRNA that was primarily detected in papillary thyroid carcinoma. However, the biological function and molecular mechanism of lncRNA PTCSC3 in glioma are still unknown.MethodsThe expression level of lncRNA PTCSC3 in human microglia and glioma cell lines was examined using quantitative real-time polymerase chain reaction (qRT-PCR). The influence of lncRNA PTCSC3 on cell proliferation were studied using the cell counting kit-8, and cell cycle and apoptosis were analyzed by flow cytometry assays. The migration and invasion abilities were investigated by transwell and wound healing assays. The target genes of lncRNA PTCSC3 were explored by qRT-PCR, immunofluorescence and western blot.ResultsLncRNA PTCSC3 was significantly downregulated in glioma cell lines. The overexpression of lncRNA PTCSC3 suppressed proliferation and induced apoptosis in U87 and U251 cells. Additionally, the overexpression of lncRNA PTCSC3 inhibited the migration and invasion of U87 and U251 cells. Moreover, lncRNA PTCSC3 inhibited the epithelial-mesenchymal transition of U87 cells. The study also demonstrated that LRP6, as a receptor of the Wnt/β-catenin pathway, was a target of lncRNA PTCSC3. By evaluating the expression levels of Axin1, active β-catenin, c-myc, and cyclin D1, the study indicated that lncRNA PTCSC3 inhibited the activation of the Wnt/β-cateninpathway through targeting LRP6.ConclusionsLncRNA PTCSC3 inhibits the proliferation and migration of glioma cells and suppresses Wnt/β-catenin signaling pathway by targeting LRP6. LncRNA PTCSC3 is a potential therapeutic target for treatment of glioma.

Fine-mapping of two differentiated thyroid carcinoma susceptibility loci at 9q22.33 and 14q13.3 detects novel candidate functional SNPs in Europeans from metropolitan France and Melanesians from New Caledonia.

Incidence of differentiated thyroid carcinoma varies considerably between countries and ethnic groups, with particularly high incidence rates in Melanesians of New Caledonia. Differentiated thyroid cancer (DTC) has a familial relative risk higher than other cancers, highlighting the contribution of inherited factors to the disease. Recently, genome-wide association studies (GWAS) identified several DTC susceptibility loci. The most robust associations were reported at loci 9q22 (rs965513 and rs1867277) and 14q13 (rs944289 and rs116909734). In this study, we performed a fine-mapping study of the two gene regions among Europeans and Melanesians from Metropolitan France and New Caledonia. We examined 81 single nucleotide polymorphisms (SNPs) at 9q22 and 561 SNPs at 14q13 in Europeans (625 cases/776 controls) and in Melanesians (244 cases/189 controls). The association with the four SNPs previously identified in GWAS was replicated in Europeans while only rs944289 was replicated in Melanesians. Among Europeans, we found that the two SNPs previously reported at 9q22 were not independently associated to DTC and that rs965513 was the predominant signal; at 14q13, we showed that the haplotype rs944289[C]-rs116909374[C]-rs999460[T] was significantly associated with DTC risk and that the association with rs116909374 differed by smoking status (p-interaction = 0.03). Among Melanesians, a new independent signal was observed at 14q13 for rs1755774 which is strongly correlated to rs2787423; this latter is potentially a functional variant. Significant interactions with parity (p < 0.05) and body mass index were observed for rs1755774 and rs2787423. This study contributed to a better characterization of the DTC loci 9q22 and 14q13 in Europeans and in Melanesians and has identified novel variants to be prioritized for further functional studies.

Identification of PTCSC3 as a Novel Locus for Large-Vessel Ischemic Stroke: A Genome-Wide Association Study.

BackgroundIschemic stroke is a major cause of death and disability in the world. A major ischemic stroke subtype, large‐vessel ischemic stroke (large artery atherosclerosis; LAA), has been shown to have some genetic components in individuals of European ancestry. However, it is not clear whether the genetic predisposition to LAA stroke varies among ethnicities. We sought to identify genetic factors that contribute to LAA stroke in 2 independent samples of Han Chinese individuals.Methods and ResultsNovel genetic variants that predispose individuals to LAA stroke were identified using a genome‐wide association study (GWAS) of 444 individuals with LAA stroke and 1727 controls in a Han Chinese population residing in Taiwan. The study was replicated in an independent Han Chinese population comprising an additional 319 cases and 1802 controls. We identified 5 single‐nucleotide polymorphisms, including rs2415317 (P=3.10×10−8), rs934075 (P=4.00×10−9), rs944289 (P=3.57×10−8), rs2787417 (P=1.76×10−8), and rs1952706 (P=2.92×10−8), at one novel locus on chromosome 14q13.3 within PTCSC3 (encoding papillary thyroid carcinoma susceptibility candidate 3) that were associated with LAA stroke at genome‐wide significance (P<5×10−8).ConclusionsOur data provide strong support for future studies on the role of PTCSC3 in the pathogenesis of LAA stroke and the association between LAA stroke development and thyroid function. In addition, these findings provide insights into the genetic basis of LAA stroke and identify a novel pathway that might be applicable for future therapeutic intervention.

Abstract TP134: Genome Wide Association Studies in Han Chinese Populations Identify Novel Susceptibility Loci for Specific Ischemic Stroke Subtypes

Introduction: Although family history studies in ischemic stroke support that genetic factors may be involved in the pathogenesis of two major subtypes of ischemia stroke: large-artery atherosclerosis (LAA) and small-vessel occlusion (SVO), it is still unclear which particular genetic factors contribute to LAA or SVO. Hypothesis: Because the etiology of ischemic stroke is heterogeneous, we hypothesize that genetic factors may vary by etiologic subtypes or ethnicities. Thus, we aim to identify genetic factors that contribute to LAA or SVO based on two independent Han Chinese populations. Methods: Novel genetic variants that predispose individuals to LAA and SVO were identified by genome-wide association study comprising of 824 individuals (including 444 LAA cases and 380 SVO cases) and 1,727 controls in a Han Chinese population residing in Taiwan. The LAA study was replicated in an independent Han Chinese population comprising of an additional 319 LAA cases and 1,802 controls. Results: In LAA cases, from two independent populations, we identified five single-nucleotide polymorphisms (SNPs), including SNP-1 (P = 3.10 х 10–8), SNP-2 (P = 4.00 х 10–9), SNP-3 (P = 3.57 х 10–8), SNP-4 (P = 1.76 х 10–8), and SNP-5 (P = 2.92 х 10–8), at one novel locus on chromosome 14q13.3 within PTCSC3 (encoding papillary thyroid carcinoma susceptibility candidate 3). In SVO cases, from the discovery stage, we identified two novel candidate susceptibility loci on chromosome 3p25.3 (SNP-6, P = 3.24 х 10–5) and chromosome 14 q31.1 (SNP-7, P = 2.58 х 10–4). Conclusions: For LAA, the newly identified SNPs within PTCSC3 gene were found to have genome-wide statistical significance (P &lt; 5 х 10–8) and were shown to be located in a risk locus correlated with papillary thyroid carcinoma. Moreover, the genetic association between PTCSC3 gene and SVO was not identified, which suggested that PTCSC3 is a specific susceptibility locus for LAA. For SVO, we identified two novel candidate genetic loci which were valuable for replication by an independent population with SVO. In conclusion, our findings provide insights into the genetic basis of LAA and SVO, which may be applicable in the study of the pathogenesis of ischemic stroke and in the development of alternative therapeutic interventions.

Association between the X-ray repair cross-complementing group 1 Arg194Trp polymorphism and thyroid carcinoma susceptibility: A meta-analysis

Previous case-control studies having investigated the relationship between the X-ray repair cross-complementing group 1 (XRCC1) Arg194Trp polymorphism and thyroid cancer (TC) have drawn inconsistent conclusions. The current study aimed to clarify the role of this polymorphism in susceptibility to TC. An up-to-date search of PubMed and Web of Science databases was conducted, including articles published up to August 2015. Crude odds ratios (ORs) with 95%CIs were calculated to establish the association between the XRCC1 Arg194Trp polymorphism and TC risk. Five studies were used, comprising 911 patients and 1476 controls. Our meta-analysis indicated that this polymorphism is associated with TC risk in Caucasians (TrpTrp vs ArgArg: OR = 5.72, 95%CI = 1.39-23.54; ArgTrp vs ArgArg: OR = 1.20, 95%CI = 0.87-1.66; dominant model: OR = 1.31, 95%CI = 0.96-1.79; recessive model: OR = 0.18, 95%CI = 0.04-0.73). This investigation demonstrates that the XRCC1 Arg194Trp polymorphism constitutes a risk factor for TC in Caucasian individuals.

Identification of epistatic interactions through genome-wide association studies in sporadic medullary and juvenile papillary thyroid carcinomas

BackgroundThe molecular mechanisms leading to sporadic medullary thyroid carcinoma (sMTC) and juvenile papillary thyroid carcinoma (PTC), two rare tumours of the thyroid gland, remain poorly understood. Genetic studies on thyroid carcinomas have been conducted, although just a few loci have been systematically associated. Given the difficulties to obtain single-loci associations, this work expands its scope to the study of epistatic interactions that could help to understand the genetic architecture of complex diseases and explain new heritable components of genetic risk.MethodsWe carried out the first screening for epistasis by Multifactor-Dimensionality Reduction (MDR) in genome-wide association study (GWAS) on sMTC and juvenile PTC, to identify the potential simultaneous involvement of pairs of variants in the disease.ResultsWe have identified two significant epistatic gene interactions in sMTC (CHFR-AC016582.2 and C8orf37-RNU1-55P) and three in juvenile PTC (RP11-648k4.2-DIO1, RP11-648k4.2-DMGDH and RP11-648k4.2-LOXL1). Interestingly, each interacting gene pair included a non-coding RNA, providing thus support to the relevance that these elements are increasingly gaining to explain carcinoma development and progression.ConclusionsOverall, this study contributes to the understanding of the genetic basis of thyroid carcinoma susceptibility in two different case scenarios such as sMTC and juvenile PTC.Electronic supplementary materialThe online version of this article (doi:10.1186/s12920-015-0160-7) contains supplementary material, which is available to authorized users.

Abstract 2042: Low Slit2 expression is associated with the aggressiveness of papillary thyroid carcinoma

Abstract Context: Slits, representative axon guidance molecules, and their Roundabout (Robo) transmembrane receptors are identified as key regulators of many cancers. One genome-wide liknage analysis suggested Slit-Robo Rho GTPase activating protein 1 gene as a candidate gene in papillary thyroid carcinoma (PTC) susceptibility. Objective: To identify the role of Slit-Robo signaling in PTC. Results : Slits(Slit 1-3) and Robos (Robo 1-4) were expressed in all of thyroid cancer cells and Slit2, Slit3, Robo1 and Robo4 presented higher expression than others. The mRNA expression of Slits and Robos was higher in fresh frozen PTC tissues than matched normal tissues. When we conducted immunohistochemical staining of Slit2 and Robo1 in thyroid tissues, the positivity of Slit2 and Robo1 were higher in PTC tissues than benign or normal tissues. However, negative Slit2 expression was significantly associated with cervical lymph node (LN) metastasis, distant metastasis and cervical recurrence of PTC (P &amp;lt;.001) irrespective of BRAF mutation status. In cellular assays, Slit2 treatment inhibited proliferation of thyroid cancer cells as dose dependent manner and also significantly suppressed cell migration by inhibiting activation of beta-catenin and inducing E-cadherin. Slit2 treatment also significantly suppressed beta-catenin activation induced by Wnt3A in luciferase reporter assay. Conclusions : Low expression of Slit2 was associated with poor prognostic factors in PTC. This present study demonstrated the potential of Slit2 as a novel prognostic and therapeutic factor in PTC. Citation Format: MinJi Jeon, Won Gu Kim, Seonhee Lim, Eun Kyung Jang, Tae Yong Kim, Young Kee Shong, Won Bae Kim. Low Slit2 expression is associated with the aggressiveness of papillary thyroid carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2042. doi:10.1158/1538-7445.AM2015-2042

Comprehensive assessment of the disputed RET Y791F variant shows no association with medullary thyroid carcinoma susceptibility.

Accurate interpretation of germline mutations of the rearranged during transfection (RET) proto-oncogene is vital for the proper recommendation of preventive thyroidectomy in medullary thyroid carcinoma (MTC)-prone carriers. To gain information regarding the most disputed variant of RET, ATA-A Y791F, we sequenced blood DNA samples from a cohort of 2904 cancer-free elderly individuals (1261 via Sanger sequencing and 1643 via whole-exome/genome sequencing). We also accessed the exome sequences of an additional 8069 individuals from non-cancer-related laboratories and public databanks as well as genetic results from the Catalogue of Somatic Mutations in Cancer (COSMIC) project. The mean allelic frequency observed in the controls was 0.0031, with higher occurrences in Central European populations (0.006/0.008). The prevalence of RET Y791F in the control databases was extremely high compared with the 40 known RET pathogenic mutations (P=0.00003), while no somatic occurrence has been reported in tumours. In this study, we report new, unrelated Brazilian individuals with germline RET Y791F-only: two tumour-free elderly controls; two individuals with sporadic MTC whose Y791F-carrying relatives did not show any evidence of tumours; and a 74-year-old phaeochromocytoma patient without MTC. Furthermore, we showed that the co-occurrence of Y791F with the strong RET C634Y mutation explains the aggressive MTC phenotypes observed in a large affected family that was initially reported as Y791F-only. Our literature review revealed that limited analyses have led to the misclassification of RET Y791F as a probable pathogenic variant and, consequently, to the occurrence of unnecessary thyroidectomies. The current study will have a substantial clinical influence, as it reveals, in a comprehensive manner, that RET Y791F only shows no association with MTC susceptibility.