Clinicopathological Features Of Papillary Thyroid Cancer Research Articles

Association of serum 25-hydroxyvitamin D levels with aggressiveness of papillary thyroid cancer.

Serum 25-hydroxyvitamin D (25(OH)D) deficiency has been known to be associated with the risk and mortality of several cancers. However, the role of 25(OH)D in papillary thyroid cancer (PTC) remains controversial. This study aimed to investigate the association between 25(OH)D and clinicopathologic features of PTC. Patients who underwent thyroidectomy were retrospectively reviewed. Serum 25(OH)D levels were measured within a week prior to surgery. The patients were categorized into four quartiles according to season-specific 25(OH)D levels. The association between 25(OH)D levels and clinicopathologic features of PTC was analyzed. A total of 2932 patients were enrolled in the study. The 25(OH)D levels were significantly higher in patients with lymph node metastasis (LNM; P < 0.001), lateral LNM (P < 0.001), and multifocal tumors (P < 0.001). Compared to the first quartile (Q1) of 25(OH)D level, the third quartile (Q3) and the fourth quartile (Q4) showed an unadjusted OR of 1.36 (95% CI: 1.09-1.69; P = 0.006) and 1.76 (95% CI: 1.42-2.19; P < 0.001) for LNM (P for trend < 0.001), respectively. An increased risk of multifocal tumors was strongly associated with high 25(OH)D concentration (P for trend <0.001). Similar results were obtained after adjusting for confounding factors. High 25(OH)D levels are associated with aggressive features of PTC, such as lymph node metastasis and multifocality.

The BRAFV600E mutation maintains the aggressiveness of papillary thyroid cancers requiring downregulation of primary cilia

Although disorders of primary cilia (PCs) were first reported in human papillary thyroid cancer (PTC) tissues in 1987, their precise role in PTC remains unclear. PCs sense the thyroid follicle colloid environment and act as a cell signaling hub. The present study investigated whether PCs are needed for BRAFV600E-driven PTC. We assessed whether BRAFV600E protein expression correlates with papillary histological architecture and clinicopathological features of PTC. We found that expression of ciliary intraflagellar transport 88 (IFT88) and PC formation were reduced in BRAFV600E-driven PTCs and that loss of cilia may be associated with lymph node metastasis. In PTC cells, the BRAFV600E mutation maintained the aggressiveness of PTC, which was partially related to loss of PCs. Our work confirms that BRAFV600E mutation-driven PC downregulation contributes to maintaining the aggressiveness of PTCs and that manipulating PC can potentially reduce the adverse incidence of PTC in a range of conditions.

PDZK1 Interacting Protein 1 Promotes the Progression of Papillary Thyroid Cancer.

The incidence of papillary thyroid cancer (PTC) has increased rapidly in recent decades, and tumor progression events are common in PTC. The purpose of our study is to identify the differentially expressed genes (DEGs) correlated with PTC progression and investigate the function of PDZK1IP1 (PDZK1 interacting protein 1) in PTC. We first analyzed DEGs associated with PTC progression between paired PTC and normal thyroid tissues in 3 Gene Expression Omnibus data sets (GSE29265, GSE33630, and GSE60542) and The Cancer Genome Atlas (TCGA) database. Data from the TCGA database and our institution were utilized to explore the relationship between PDZK1IP1 expression and clinicopathological characteristics of PTC. The CCK8 cell proliferation assay, clone formation assay, flow cytometry assay, and the xenograft model were used to investigate the function of PDZK1IP1 in PTC. Thirty-nine DEGs associated with PTC progression were identified, in which only PDZK1IP1 was upregulated in PTC tissue at both messenger RNA and protein levels. In addition, we found that high expression of PDZK1IP1 in the TCGA database was associated with poor progression-free survival, extrathyroidal extension, high stage, tall cell variant, and BRAFV600E mutation of the PTC (P < 0.001). In our collected samples, high expression of PDZK1IP1 was only related to lymph node metastasis (P < 0.05). Overexpression of PDZK1IP1 significantly promoted proliferation and inhibited apoptosis of PTC cells. Knockdown of PDZK1IP1 significantly inhibited proliferation, promoted apoptosis, and prevented xenograft formation of PTC cells. PDZK1IP1 is an oncogene for tumorigenesis and development of PTC and might be a potential therapeutic target.

Low urinary iodine is a protective factor of central lymph node metastasis in papillary thyroid cancer: a cross-sectional study

BackgroundAn abrupt increase of thyroid cancer has been witnessed paralleling the supplemented iodine intake in formerly iodine-deficient countries. And increased iodine intake has been linked to the rising incidence rate of papillary thyroid cancer (PTC). However, the correlation between iodine and clinicopathological features of PTC has not been well-characterized. This study aimed to investigate the associations between iodine intake and the clinicopathological features of PTC patients.MethodsThree hundred and fifty-nine PTC patients who received surgical treatment in Peking Union Medical College Hospital from May 2015 to November 2020 were retrospectively reviewed. The associations between urinary iodine (UI), urinary iodine/creatinine ratio (UI/U-Cr), and the clinicopathological features of PTC were analyzed. Univariate and multivariate analysis were performed to investigate the relationship between UI level and central lymph node metastasis (CLNM).ResultsThere were no significant differences in UI in different groups according to the variables studied, except that patients with CLNM had higher UI level than CLNM(−) patients. No associations were found between UI/U-Cr and clinicopathological features except variant subtypes (classic/follicular). After dividing patients into high-iodine group and low-iodine group, more patients were found to have CLNM in the high-iodine group (p = 0.02). In addition, younger age, larger tumor size, and classic variant were positively correlated with CLNM (p < 0.05). Univariate analysis showed that insufficient iodine intake (≤ 99 μg/L) was associated with decreased CLNM risk in PTC. And after defining insufficient iodine intake as ≤ 109 μg/L and above requirements as ≥ 190 μg/L, multivariate analysis showed that lower iodine was associated with CLNM in total population of PTC (OR 0.53, 95% CI 0.31–0.91) and in PTC < 1 cm (papillary thyroid microcarcinoma, PTMC) (OR 0.43, 95% CI 0.21–0.87).ConclusionsLow iodine was a protective factor for CLNM in papillary thyroid cancer, particularly in those < 1 cm. These results indicated that iodine may not only be an initiator of tumorigenesis, but also a promoter of the development of PTC.

TNRC6C Functions as a Tumor Suppressor and Is Frequently Downregulated in Papillary Thyroid Cancer.

Our previous study found that trinucleotide repeat containing adaptor 6C (TNRC6C) may act as a tumor suppressor in papillary thyroid cancer (PTC). In this study, we aimed to confirm the effect of TNRC6C on PTC and investigate the underlying molecular mechanism. The difference of mRNA level of TNRC6C between PTC tissue and noncancerous thyroid tissue and the association of expression level of TNRC6C with clinicopathological features of PTC were analyzed using TCGA data. Immunohistochemical assay was performed to detect the protein expression of TNRC6C in PTC and its adjacent noncancerous tissue. Cell proliferation, migration, invasion, and apoptosis were analyzed after knockdown or overexpression of TNRC6C in BCPAP cells. RNA-sequencing was performed to find the target genes of TNRC6C, and potential targets were validated in BCPAP and TPC1 cells. Our results showed that TNRC6C was downregulated in PTC, and lower expression level of TNRC6C was associated with worse clinicopathological features. Overexpression of TNRC6C significantly inhibited proliferation, migration, and invasion of BCPAP cells and promoted its apoptosis, while knockdown of TNRC6C acted the opposite role. By analyzing RNA-sequencing data and TCGA data, 12 genes (SCD, CRLF1, APCDD1L, CTHRC1, PTPRU, ALDH1A3, VCAN, TNC, ECE1, COL1A1, CAMK2N2, and MMP14) were considered as potential target genes of TNRC6C, and most of them were associated with clinicopathological features of PTC in TCGA. All of them except CAMK2N2 were significantly downregulated after overexpressing TNRC6C. Our study demonstrated that TNRC6C functions as a tumor suppressor in PTC and may serve as a useful therapeutic target and prognostic marker for PTC patients.

Positive Thyroid Peroxidase Antibody and Thyroglobulin Antibody are Associated With Better Clinicopathologic Features of Papillary Thyroid Cancer

ObjectiveTo compare the thyroid autoantibody status of patients with papillary thyroid cancer (PTC) and benign nodular goiter as well as possible associations between thyroid autoantibodies and clinicopathologic features of PTC. MethodsA total of 3934 participants who underwent thyroidectomy were enrolled in this retrospective study. Patients were divided into PTC and benign nodule groups according to pathological diagnosis. Based on the preoperative serum antibody results, PTC patients were divided into thyroid peroxidase antibody (TPOAb)-positive, thyroglobulin antibody (TgAb)-positive, dual TPOAb- and TgAb-positive, or antibody-negative groups. ResultsOf the 3934 enrolled patients, 2926 (74.4%) were diagnosed with PTC. Multivariate regression analyses suggested that high thyroid-stimulating hormone levels (adjusted odds ratio [OR] = 1.732, 95% CI [1.485-2.021], P < .001), positive TgAb (adjusted OR = 1.768, 95% CI [1.436-2.178], P < .001), and positive TPOAb (adjusted OR = 1.452, 95% CI [1.148-1.836], P = .002) were independent risk factors for predicting malignancy of thyroid nodules. Multinomial multiple logistic regression analyses indicated that positive TPOAb alone was an independent predictor of less central lymph node metastasis in PTC patients (adjusted OR = 0.643, 95% CI [0.448-0.923], P = .017), whereas positive TgAb alone was significantly associated with less extrathyroidal extension (adjusted OR = 0.778, 95% CI [0.622-0.974], P = .028). PTC patients with dual-positive TPOAb and TgAb displayed a decreased incidence of extrathyroidal extension (adjusted OR = 0.767, 95% CI [0.623-0.944], P = .012) and central lymph node metastasis (adjusted OR = 0.784, 95% CI [0.624-0.986], P = .037). ConclusionAlthough preoperative positive TPOAb and TgAb are independent predictive markers for PTC, they are also associated with better clinicopathologic features of PTC.

Immortalization up-regulated protein promotes tumorigenesis and inhibits apoptosis of papillary thyroid cancer.

The incidence of thyroid cancer is increasing in recent years worldwide, but the underlying mechanisms await further exploration. We utilized the bioinformatic analysis to discover that Immortalization up‐regulated protein (IMUP) could be a potential oncogene in the papillary thyroid cancer (PTC). We verified this finding in several databases and locally validated cohorts. Clinicopathological features analyses showed that high expression of IMUP is positively related to malignant clinicopathological features in PTC. Braf‐like PTC patients with higher IMUP expression had shorter disease‐free survival. The biological function of IMUP in PTC cell lines (KTC‐1 and TPC‐1) was investigated using small interfering RNA. Our results showed that silencing IMUP suppresses proliferation, migration and invasion while inducing apoptosis in PTC cell lines. Changes of the expression of apoptosis‐related molecules were identified by real‐time quantitative polymerase chain reaction and Western blotting. We also found that YAP1 and TAZ, the critical effectors in the Hippo pathway, were down‐regulated when the IMUP is silenced. Rescue experiments showed that overexpression of YAP1 reverses the tumour inhibitory effect caused by IMUP knockdown. Our study demonstrated that IMUP has an oncogenic function in PTC and might be a new target gene in the treatment of PTC.

KCNN4 is a diagnostic and prognostic biomarker that promotes papillary thyroid cancer progression.

The incidence of thyroid cancer remains high worldwide, and papillary thyroid cancer (PTC) is the most common type. Potassium Calcium-Activated Channel Subfamily N Member 4 (KCNN4) has been reported as an oncogene in various cancers. We examined expression of KCNN4 in public databases and discovered that it is upregulated in PTC. We verified this finding using our own validated cohort and RNA sequencing data. We also found that KCNN4 is a diagnostic and prognostic biomarker that is associated with disease-free survival, immune infiltration, and several other clinicopathological features of PTC. Gene Set Enrichment Analysis indicated that apoptotic and epithelial-mesenchymal transition gene sets are both upregulated in PTC patients with higher KCNN4 levels. In PTC cell lines, silencing KCNN4 inhibited cell proliferation, migration and invasion. Moreover, quantitative real-time PCR and Western blotting indicated that silencing KCNN4 increased expression of apoptotic genes in PTC cells and reduced the expression of genes involved in their epithelial-mesenchymal transition. These results suggest that KCNN4 promotes PTC progression by inducing epithelial-mesenchymal transition and suppressing apoptosis, which suggests KCNN4 may be a useful diagnostic and prognostic biomarker of PTC.

Expression of fatty acid 2-hydroxylase as a novel prognostic factor in papillary thyroid cancer

Objective To examine the expression levels of fatty acid 2-hydroxylase (FA2H) mRNA in papillary thyroid cancer (PTC) tissue samples and evaluate the relationship between FA2H and the clinicopathological characteristics and overall survival (OS) in PTC. Methods Real-time quantitative polymerase chain reaction (Real-time PCR) was used to detected the expression levels of FAH2 in PTC and normal samples. The correlation between FA2H and the clinicopathological features in PTC was analyzed. Online Kaplan-Meier database was used to explore the effects of FA2H on survival of PTC patients. Results The FA2H levels were higher in PTC cancer tissues than those in normal tissues in PTC (3.86±0.27 vs. 1.00±0.16, t=10.033, P<0.01). FA2H levels were correlated to T stage, N stage and TNM positively (χ2=5.570, 6.169 and 6.508, P<0.05). OS rate of PTC patients with higher levels of FA2H were shorter than those with higher levels of FA2H expression (P<0.05). Conclusion FA2H was upregulated in PTC cancer tissues, and related to tumor size, lymph node metastasis and TNM stage positively. Increased expression of FA2H is related to shorter OS in PTC. Key words: Papillary thyroid cancer; Fatty acid 2-hydroxylase

Transcriptome Analyses Identify a Metabolic Gene Signature Indicative of Dedifferentiation of Papillary Thyroid Cancer.

Metabolic reprogramming is a common feature of tumorigenesis. It remains unknown concerning the expression pattern of metabolism-associated genes in dedifferentiated thyroid cancer (DDTC). This study aimed to identify a useful signature to indicate dedifferentiation of papillary thyroid cancer (PTC). We used one discovery and two validation cohorts to screen out aberrant metabolic genes in DDTC, and further used The Cancer Genome Atlas (TCGA) cohort to search for independent risk factors for the low-differentiated phenotype of PTC as a signature of dedifferentiation. The prediction of the signature for DDTC was validated in the TCGA cohort and the combined Gene Expression Omnibus cohort. We also analyzed the correlations of the signature risk score with clinicopathological features of PTC. Gene set enrichment analyses were performed in the TCGA cohort. Significant enrichment of metabolic pathways correlated with differentiation status of PTC. A signature of metabolic genes including LPCAT2, ACOT7, HSD17B8, PDE8B, and ST3GAL1 was discovered and validated across three cohorts. The signature was not only predictive of DDTC but also significantly associated with BRAFV600E mutation (P < 0.001), T3/T4 stage (P < 0.001), extrathyroidal extension (P < 0.001), lymph node metastasis (P < 0.001), and tumor/lymph node/metastasis III/IV stage (P < 0.001) in PTC. Downregulations of LPCAT2 expression (P = 0.009) and ST3GAL1 expression (P = 0.005) increased risks of decreased disease-free survival for patients. Furthermore, the signature was implicated in a number of oncogenic biological pathways. Our findings suggest that metabolic deregulations mediate dedifferentiation of PTC, and that the metabolic gene signature can be used as a biomarker for DDTC.

NECTIN4 promotes papillary thyroid cancer cell proliferation, migration, and invasion and triggers EMT by activating AKT.

Papillary thyroid cancer (PTC) is the most frequent type of malignant thyroid cancer, but its molecular mechanisms remain unknown. To better understand the tumorigenesis and progression of PTC, we conducted a comprehensive analysis of the whole-transcriptome resequencing of paired PTC and normal thyroid tissues. Nectin cell adhesion molecule 4 (NECTIN4) was significantly overexpressed in thyroid carcinoma compared with that in matched normal tissue. We also assessed the relation between the expression level of NECTIN4 and the clinicopathological features of PTC in The Cancer Genome Atlas database, and results showed that upregulated NECTIN4 is associated with lymph node metastasis (P<0.001) and tumor size (P=0.017). The biological function of NECTIN4 was also investigated by using the PTC cell lines TPC-1 and KTC-1. In vitro experiments demonstrated that NECTIN4 downregulation significantly inhibits the colony formation, proliferation, migration, and invasion of PTC cell lines. NECTIN4 could modulate the expression of epithelial–mesenchymal transition-related proteins via the PI3K/AKT pathway, and SC79, an AKT phosphorylation activator, could reverse the si-RNA knockdown effect. In addition, after the use of AKT inhibitors (LY 294,002), we found that SiRNA have similar effect with AKT inhibitors. Taking the results together, the current study shows that NECTIN4 has important biological implications in the tumorigenesis and metastasis of PTC and may be a potential therapeutic target for the disease.

Aberrant hypermethylation of the HOXD10 gene in papillary thyroid cancer with BRAFV600E mutation.

Epigenetic abnormalities as well as genetic abnormalities may play a vital role in the tumorigenesis of papillary thyroid cancer (PTC). The present study aimed to analyze the function and methylation status of the HOXD10 gene in PTC and aimed to identify relationships between HOXD10 methylation, HOXD10 expression, BRAF mutation and clinicopathological characteristics of PTC. A total of 152 PTC patients were enrolled in the present study. The methylation status of the HOXD10 promoter was analyzed by quantitative methylation-specific polymerase chain reaction (Q-MSP). BRAFV600E mutation status was analyzed by polymerase chain reaction (PCR) followed by DNA sequencing. HOXD10 mRNA expression level was analyzed by real-time polymerase chain reaction (RT-PCR). 5-Aza-2-deoxycytidine (5-Aza) treatment was performed in 4PTC cell lines to observe the change in HOXD10 expression. Transwell, cellcycle and apoptosis assays were then performed in an HOXD10-overexpressing PTC cell line. Furthermore, we analyzed the associations between HOXD10 methylation, HOXD10 expression, BRAF mutation and clinicopathological characteristics in PTC. Overexpression of HOXD10 suppressed the migration of PTC cells, and promoted cell apoptosis. Q-MSP showed that methylation levels of the HOXD10 promoter were significantly higher in PTC tissues than levels in the adjacent normal thyroid tissues (P=0.02). In addition, expression of HOXD10 was decreased in the PTC cell lines and PTC tissues compared with that noted in the adjacent normal thyroid tissues(P=0.008). However, BRAFV600E mutation was detected in 42.1% of PTC patients enrolled. In addition, the BRAF mutation status was associated with the methylation and expression level of HOXD10 in PTC. We then observed that 5-Aza treatment could revert the expression of HOXD10 in PTC cell lines. Moreover, the hypermethylation of HOXD10 was associated with invasion of the primary tumor and age>45. In conclusion, the HOXD10 gene may act as a tumor suppressor in PTC. The aberrant hypermethylation and decreased expression of the HOXD10 gene were shown in PTC patients, particularly in those with BRAFV600E mutation. The epigenetic suppression of the HOXD10 gene may play a role in the tumorigenesis of PTC, and it is a prospective biomarker for the diagnosis and prognosis of PTC.

BRAF(V600E) Mutation is Associated with Decreased Disease-Free Survival in Papillary Thyroid Cancer.

The BRAF (V600E) mutation is a recognised molecular marker in papillary thyroid cancer (PTC), reported incidence from 30 to 80%. BRAF(V600E) aberrantly activates the MAPK pathway, a central regulator of cell growth and proliferation. Previous studies have reported conflicting data regarding the impact of BRAF(V600E) on clinicopathological features of PTC. The study aims to determine whether BRAF(V600E) is useful as a prognostic biomarker in PTC. A cohort study of patients undergoing surgery for PTC was undertaken. The primary outcome measure was disease-free survival. Secondary outcome measures were tumour size, nodal positivity and radioactive iodine ablation rate. All cases were re-examined to confirm PTC. Immunohistochemistry for BRAF(V600E) was performed on tissue microarrays. A single endocrine pathologist, blinded to clinicopathological data, interpreted staining. 496 patients with PTC were included, and 309 (62%) were BRAF(V600E) positive. Tumour size was similar for BRAF(V600E)-positive and -negative tumours (21.3 vs. 23.2mm, p=0.23). BRAF(V600E)-positive patients were significantly older at first operation (mean age 45 versus 49years, p=0.003). BRAF(V600E)-positive PTCs had a higher rate of disease recurrence (12.9 vs. 5.6%, p=0.004), lymph node metastasis (44 vs. 29.4%, p=0.004) and extra-thyroidal extension (44 vs. 22%, p<0.001). Five-year disease-free survival was 89.6% for BRAF(V600E) positive and 96.3% for negative tumours, p<0.001. There was no difference between groups for vascular invasion or multifocality. The mean follow-up was 57months for both groups. BRAF(V600E) in PTC predicts an increased risk of lymph node metastasis, extra-thyroidal extension and reduced disease-free survival. It is an additional useful prognostic biomarker.

Association Between Obesity and BRAFV600E Mutation Status in Patients with Papillary Thyroid Cancer.

The prevalence of papillary thyroid cancer (PTC) is thought to be related to obesity, which affects the prognosis for PTC patients. However, the mechanisms implicated in the relationship between obesity and PTC is a matter for debate. In this study, we aimed to gain insight into the relationship between obesity and the clinicopathological features of PTC, including the BRAFV600E mutation. The medical records of 1121 PTC patients were reviewed and the relationships between anthropometric factors, biochemical parameters, and clinicopathological parameters, including BRAFV600E mutation status, were analyzed. Body mass index (BMI) showed a strong association with advanced TNM stage (p < 0.001) and BRAFV600E mutation status (p = 0.008). We also found that BRAFV600E (+) patients had a higher body weight (p = 0.024) and a higher BMI (p = 0.003) than patients with BRAFV600E (-) PTC. In addition, BRAFV600E (+) PTC patients had a significantly higher incidence of extrathyroidal extension (p = 0.025) and more advanced T, N, TNM stage (p < 0.001) than BRAFV600E (-) PTC patients. Consistent with this observation, female BRAFV600E (+) PTC patients had a higher BMI (p = 0.011) and more aggressive tumor behaviors than female BRAFV600E (-) PTC patients. In multivariate analysis, BMI was persistently associated with BRAFV600E mutation in the entire cohort (odds ratio [OR] 1.387; 95 % CI 1.036-1.859; p = 0.028) and in the female subcohort (OR 1.221; 95 % CI 1.014-1.631; p = 0.046). The positive association between BMI and BRAFV600E supports the hypothesis that excessive bodyweight influences tumor progression.

Expression of YY1 in Differentiated Thyroid Cancer.

The transcription factor Yin Yang 1 (YY1) has an important regulatory role in tumorigenesis, but its implication in thyroid cancer has not been yet investigated. In the present study, we have analyzed the expression of YY1 in differentiated thyroid cancer and assessed the association of YY1 expression with clinical features. Expression of YY1 was evaluated in human thyroid cancer cell lines, a series of matched normal/tumor thyroid tissues and in a thyroid cancer tissue microarray, using real-time PCR, Western blot, and/or immunohistochemistry. YY1 was overexpressed in thyroid cancer cells, at transcription and protein levels. A significant increase of YY1 mRNA was also observed in tumor thyroid tissues. Moreover, immunohistochemical analysis of the thyroid cancer tissue microarray revealed that both papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC) present increased YY1 protein levels (48 and 19%, respectively). After stratification by the level of YY1 protein, positive YY1 expression identifies 88% of patients with PTC. The association of YY1 expression with clinicopathological features in PTC and FTC showed that YY1 expression was related with age at diagnosis. Our data indicates for the first time overexpression of YY1 in differentiated thyroid cancer, with YY1 being more frequently overexpressed in the PTC subtype.

Clinical significance of papillary thyroid cancer risk loci identified by genome-wide association studies

Four single nucleotide polymorphisms (SNPs) have been reported to be associated with thyroid cancer risk in two genome-wide association studies (GWASs) and were validated in a Chinese population. Because of a lack of further clinical and functional evidence, the clinical significances of these SNPs remain unknown. Four GWAS-identified SNPs of papillary thyroid cancer (PTC), rs965513, rs944289, rs966423 and rs2439302, were genotyped in a case-control study of 838 patients with PTC and 501 patients with benign thyroid tumor (BTT) from the Chinese Han population. The associations between these SNPs, clinicopathologic features, and the outcome of the PTC patients were examined. The CT and CT + TT genotypes of rs966423 were more common in PTC patients with extrathyroidal extension and more advanced T stage. The TC and TC + CC genotypes and the C allele of rs944289 were significantly less frequent in patients with multifocal disease. No correlation was observed between GWAS-identified SNPs and disease persistence of PTC after a short-term follow-up. Significantly different allele distributions between the PTC and BTT groups were observed for all four selected SNPs. Individuals with more than five risk alleles were 8.84-fold (95% CI 3.23-24.17) more likely to suffer from PTC compared with those with zero or 1 risk allele. GWAS-identified SNPs affect the individual predisposition to PTC without interacting with existing Hashimoto thyroiditis and BTT lesions. GWAS-identified SNPs were associated with certain clinicopathologic features of PTC, and may contribute to identifying PTC patients with different clinical patterns. Large prospective studies are required to further evaluate the diagnostic and prognostic power of these genetic markers.

Association between interleukin 17/interleukin 17 receptor gene polymorphisms and papillary thyroid cancer in Korean population

BackgroundAlthough numerous recent studies have implicated a role for interleukin 17(IL17) in tumor development, the mechanisms of IL17 involvement are still uncharacterized. The aims of this study were to determine whether single nucleotide polymorphisms (SNPs) in IL17 and IL17R contribute to the development of papillary thyroid cancer (PTC) and to assess the relationship between IL17 and IL17R SNPs and the clinicopathologic characteristics of PTC. Materials and methodsEight SNPs located within the IL17A, IL17RA, and IL17RB genes were genotyped using direct sequencing in 94 patients with PTC and 260 patients without PTC (controls). Genetic data were analyzed using commercially available software. Statistical analyses were then performed to examine the relationships between these SNPs and the clinicopathologic characteristics of PTC. ResultsGenotyping analysis demonstrated that the IL17RA SNP rs4819554 (codominant model 1, odds ratio (OR)=0.39, P=0.001) and the IL17RB SNP rs1025689 (dominant model, OR=0.59, P=0.043) were significantly associated with lack of PTC. Interestingly, the IL17A SNP rs2275913 (codominant model 2, OR=0.19, P=0.034) was significantly associated with lack of multifocality. Furthermore, the IL17RA SNP rs4819554 (dominant model, OR=0.25, P=0.010) was significantly associated with lack of cancer bilaterality. ConclusionIn this study of SNPs in the IL17 and IL17R genes in patients with PTC, we demonstrated that IL17RA polymorphisms can influence both the development and the bilaterality of PTC.

Low Serum 25 Hydroxyvitamin D Is Associated with Poor Clinicopathologic Characteristics in Female Patients with Papillary Thyroid Cancer

Vitamin D has recently attracted attention because reduced levels are associated with the prevalence and aggressiveness of several cancers. This study aimed to evaluate the relationship between preoperative serum 25 hydroxyvitamin D (25(OH) vitamin D) levels and clinicopathologic characteristics in female patients with papillary thyroid cancer (PTC). A total of 548 female patients who underwent total thyroidectomy for PTC between June 2012 and May 2013 were included. Blood samples were obtained within two weeks prior to surgery. Patients were categorized into four quartiles by preoperative serum 25(OH) vitamin D levels. The clinicopathologic features of PTC were analyzed retrospectively. Preoperative 25(OH) vitamin D was significantly lower in patients with a tumor size of >1 cm (p = 0.041) or lymph node metastasis (LNM; p = 0.043). No significant trends in several clinicopathologic features were observed in relation to increasing serum vitamin D concentrations except decreasing tumor size (p = 0.010). Patients in the second quartile had a greater occurrence of T stage 3/4 (odds ratio (OR) 2.03 [confidence interval (CI) 1.19-3.44]; p = 0.009), LNM (OR 2.03 [CI 1.19-3.44]; p = 0.009), lateral LNM (OR 5.03 [CI 1.66-15.28]; p = 0.004), and extrathyroidal extension (ETE; OR 1.95 [CI 1.15-3.29]; p = 0.013) than those in the fourth quartile. Multivariate analysis showed that patients in the second quartile had a greater occurrence of T stage 3/4 (OR 1.89 [CI 1.08-3.30]; p = 0.026), LNM (OR 2.04 [CI 1.20-3.47]; p = 0.009), lateral LNM (OR 5.12 [CI 1.68-15.59]; p = 0.004), and ETE (OR 1.81 [CI 1.04-3.15]; p = 0.036) than those in the fourth quartile. When the subjects were recategorized into two groups by median 25(OH) vitamin D levels, those with values below the median had a significantly higher risk of T stage 3/4, LNM, lateral LNM, stage III/IV, and ETE. All values except ETE sustained significance after adjustment. Lower preoperative serum 25(OH) vitamin D levels appear to be associated with poor clinicopathologic features in female patients with PTC.

A Fas-Associated via Death Domain Promoter Polymorphism (rs10898853, -16C/T) as a Risk Factor for Papillary Thyroid Cancer

Purpose: To determine whether a Fas-associated via death domain (FADD) promoter single-nucleotide polymorphism (SNP) is associated with susceptibility to papillary thyroid cancer (PTC) and clinicopathological features of PTC. Methods: To identify a possible association with PTC, 94 patients with PTC and 346 healthy controls were recruited. One promoter SNP (rs10898853, -16C/T) was analyzed by direct sequencing. Multiple logistic regression models (co-dominant, dominant, recessive, and log-additive models) were applied, and odds ratios (ORs), 95% confidence intervals (CIs), and p values were calculated. Results: The genotype of the promoter SNP (rs10898853) of FADD was found to be significantly associated with PTC in the co-dominant model 2 (T/T vs. C/C; p = 0.002, OR = 2.80, 95% CI = 1.39-5.65), the recessive model (p = 0.003, OR = 2.21, 95% CI = 1.31-3.71), and the log-additive model (p = 0.002, OR = 1.71, 95% CI = 1.20-2.44). Allele frequency analysis showed that the C allele of rs10898853 was significantly associated with an increased risk of PTC (p = 0.002, OR = 1.67, 95% CI = 1.21-2.32). Conclusions: Our results suggest that the FADD promoter polymorphism is associated with susceptibility to PTC.

Midkine expression is associated with clinicopathological features and BRAF mutation in papillary thyroid cancer

The objective of this study is to detect the expression of midkine (MK) in papillary thyroid cancer (PTC) and to evaluate whether MK expression is associated with clinicopathological features and BRAF mutation in PTC. The expression of MK in samples from 200 cases of PTC, 60 cases of adenomatoid nodule of thyroid, and 40 samples of tumor-adjacent normal thyroid tissue were assessed with immunohistochemistry. The BRAF mutation was detected by direct sequencing. The relationships between MK expression and the clinicopathological features of PTC and BRAF mutation were analyzed. The results demonstrated that MK was not expressed in tumor-adjacent normal tissue. The positive expression rates and MK scores were both higher in PTC than in adenomatoid nodule (positive expression rates: 88 vs. 8.3 %, P < 0.001; MK scores: 2.02 ± 0.93 vs. 0.08 ± 0.28, P < 0.001). The expression level of MK in PTC with extrathyroidal invasion, lymph node metastasis, or stage III/IV was significantly higher than that in PTC without such biological features (all P < 0.01). The overall prevalence of BRAF mutation was 66.5 % in PTC. The expression level of MK in PTC with BRAF mutation was significantly higher than that in PTC with wild-type BRAF (P < 0.001). We can conclude that MK is specifically expressed in PTC tissues and is associated with clinicopathological features and BRAF mutation. MK may be a helpful diagnostic and prognostic marker for PTC.