The Clinical And Basic Research On The Relationship Between TSH And Papillary Thyroid Cancer

Part Ⅰ:The Predictor Value of Preoperative Serum Thyroid Stimulating Hormone for Papillary Thyroid Cancer in Nodular Thyroid DiseaseWe conducted a systemic retrospective study of 4639 patients from 2007 to 2009, including 2581 patients with benign nodule,2058 with PTC. The independence of serum TSH risk and thyroidglobulin antibody (TgAb) risk was evaluated by logistic regression. Calibration of the risks was evaluated using the Hosmer-Lemeshow test. The predictor models based on TSH and TSH+TgAb were evaluated using receiver operating characteristic curves. Preoperative serum TSH is a independent factor on risk of PTC in NTD. Meanwhile, serum TgAb is a risk fact for the PTC. We observed an AUC of 0.834 (95% CI,0.823-0.846) for the TSH+TgAb model risk compared with AUC of 0.805 (95% CI,0.792-0.817) for TSH model. There is a strong positive correlation effect of preoperative serum TSH on probability of PTC in NTD. The TSH suppress therapy might be used in the NTD patients whose serum TSH are high. The model based on TSH has a remarkable value in predicting the risk of PTC. Multicenter research is recommended to verify the predictor model based on TSH.Part Ⅱ:The clinical features of papillary thyroid cancer in Hashimoto’s thyroiditis patients from an area with a high prevalence of Hashimoto’s diseaseTo identify the clinicopathological factors of co-existing papillary thyroid cancer (PTC) in patients with Hashimoto’s thyroiditis (HT) and provide information to aid in the diagnosis of such patients. This study included 6109 patients treated in a university-based tertiary care cancer hospital over a 3-year period. All the patients were categorized based on their final diagnosis. Several clinicopathological factors, such as age, gender, nodular size, invasive status, central compartment lymph node metastasis (CLNM) and serum thyroid stimulating hormone (TSH) level, were compared between the various groups of patients. There were 653 patients with a final diagnosis of HT. More PTC was found in those with HT (381 out of 653 or 58.3%) than in those without HT (2416 out of 5456 or 44.3%, p< 0.05). The HT patients with co-occurring PTC were more likely to be younger, female, have smaller nodules and have higher TSH levels than those without PTC. A multivariate analysis demonstrated that the presence of HT and higher TSH levels were risk factors for a diagnosis of PTC. In the PTC patients, moreover, the presence of HT or other benign nodule was a protective factor for CLNM, while the TSH level had no significant associations.Part III:The Polymorphisms of FOXE1 in TSH-cAMP-FOXE1 pathway in the occurence of papillary thyroid cancerThyoid cancer is the most popular endocrine malignant, which is the 7th cancer in women, and about 90% thyoid cancer is papillary thyroid cancer. Recently reasearches show high level thyroid stimulating hormone (TSH) causes higher risk of thyroid cancer. In our research, we confirm this phenomenon in Chinese patients. Unfortunately, the molecular mechanism of how TSH-cAMP pathway casused thyroid cancer was unclear, we find FOXE1 gene:rs1867277(A>G),rs907577(C>T) and rs3758248(C>T) are the suspective SNP of papillary thyroid cancer. TSH could cause the risk higher in these patients. In future study, we will analysis the genetic variant of FOXE1 under the stimulation of TSH, and furthermore we will investigate the differentiation and proliferation of thyroid follicle cell under TSH stiumlation.Part IV:Aberrant hypermethylation and increased expression of the FOXE1 gene in papillary thyroid cancerThe methylation status of FOXE1 was analyzed by bisulfite-sequencing PCR (BSP) in W3, TPC1, IHH-4 and Nthy-ori 3-1 cell lines. In total,111 paired clinical thyroid tumors (79 PTC and 32 benign thyroid tumors) and adjacent normal thyroid samples were analyzed by methylation-specific PCR (MSP). FOXE1 mRNA expression levels were analyzed by real-time polymerase chain reaction (qRT-PCR). The genotype of BRAF V600E was detected in PTC samples by direct sequencing. We noted a significant difference in the methylation level of FOXE1 in PTC (5.06%) and benign thyroid tumors compared with paired adjacent normal thyroid tissues (16.46%) (p=0.040). Hypomethylation in the promoter region of FOXE1 was significantly associated with its increased expression in PTC (p<0.050). In addition, the methylation status of FOXE1 was significantly associated with Hashimoto’s thyroiditis (HT) (p=0.003), the T stage of patients (p<0.001) and the capsular invasion (CI) of PTC (p<0.001). No statistically significant association was identified between the BRAF V600E mutation and the DN A methylation pattern in FOXE1. Epigenetic inactivation of the FOXE1 gene plays a potentially important role in PTC, and it might be a prospective biomarker for the diagnosis of PTC.