| Part one: A distinct serum metabolic signature of distant metastatic papillary thyroid carcinomaObjective Although the incidence rates for thyroid cancer seem to have begun stabilizing in recent years,increased rates of advanced stage of this disease have been reported.In addition,the status of distant metastasis plays the most important role in the prognosis of patients with papillary thyroid carcinoma(PTC).Unfortunately,the underlying mechanisms of distant metastasis as well as cell status including metabolism changes in distant metastatic tumors have not been clearly elucidated.Methods In this study,gas chromatography time-of-flight mass spectrometry(GC-TOF-MS)was used to analyze 77 PTC patients(37 in distant metastasis group and 40 in ablation group).Results Principal component analysis(PCA)and orthogonal partial least-squares-discriminant analysis(OPLS-DA)scores plots demonstrated an evident trend of separation between 40 serum samples from the ablation group and 37 samples from distant metastasis group.A total of 31 metabolites were identified which are related to amino acid,lipid,glucose,vitamin metabolism and diet/gut microbiota interaction.A pathway analysis showed ‘alanine,aspartate and glutamate metabolism’ and ‘inositol phosphate metabolism’ were the most relevant pathways.Conclusion Serum metabolomics profiling could significantly discriminate papillary thyroid cancer patients according to distant metastasis.Potential metabolic aberration in distant metastatic PTC could be involved in different biologic behaviors of tumor cells including proliferation,invasion/migration,and immune escape.Diet/gut microbiota produced metabolites could play an important role in these effects.This work may provide new clues of the underlying mechanisms regarding to the distant metastasis of PTC as well as potential adjuvant therapy targets.Part two: Association between thyroid autoimmune antibodies and disease statuses of papillary thyroid carcinomaObjective The relationship between thyroid autoimmunity and thyroid cancer remains controversial.The objective of this study is to comprehensively analyze the association between thyroid autoimmune antibodies and disease statuses of papillary thyroid carcinoma(PTC).Methods Patients were divided into different groups according to their final diagnoses after radioiodine therapy and their serum anti-thyroglobulin antibody(TgAb)and anti-thyroid peroxidase antibody(TPOAb)titers.Clinicopathologic characteristics were then compared between groups.Results In all,1126 PTC patients met the inclusion criteria.When compared to thyroid autoimmune antibody negative group,patients in positive group were young female predominant.After age and gender adjusted,patients in thyroid autoimmune antibody positive group had much more cervical metastatic node count and this effect was limited to the central compartment but not to the lateral compartment.Antibody positivity rate was much lower in patients with distant metastasis and multivariable logistic regression analysis showed positive status of antibody was a protective factor of distant metastasis of PTC with an OR value of 0.403(95% CI: 0.216-0.622,p <0.001).Additionally,subgroup analysis demonstrated single TgAb positivity and combined positivity of TgAb and TPOAb were shown to be related to less distant metastatic disease.Conclusion Positive thyroid auto-antibody status could be a risk factor of more metastatic cervical lymph nodes while a protective factor of distant metastatic disease in PTC patients.The association between thyroid autoimmunity and thyroid cancer can be patient and antibody specific.A systemic immunosuppression status may exist in PTC patients with distant metastasis.Part three: Potential association between targeted genes and papillary thyroid carcinoma predisposition as well as disease progression using targeted next generation sequencingObjective The purpose of this study was to use next generation sequencing technique to explore the potential association between 14 targeted genes(BRAF,KRAS,NRAS,HRAS,TERT,HABP2,EIF1 AX,PPM1D,CHEK2,S100A7,NLRP6,NUP93,GAS8-AS1 and LPAR4)and papillary thyroid carcinoma(PTC)predisposition as well as disease progression.Methods In all,516 subjects were selected and included in this study composing of416 PTC patients and 100 healthy controls.According to their final diagnosis,PTC patients were divided into distant metastasis group and non-distant metastasis group.Patients in distant metastasis group were further divided into radioiodine-refractory PTC(RR-PTC)and non-RR-PTC depend on their response to radioiodine therapy.Genomic DNA was extracted from peripheral blood sample and MiSeq Benchtop Sequencer(Illumina,Inc,San Diego,CA)was used for sequencing.Results We found that rs11246050 in NLRP6(dominant model,OR/95%CI:2.028/1.091-3.769,p=0.025),rs2286742 and rs3740530 in HABP2(recessive model,OR/95%CI: 9.644/1.307-71.16,p=0.026 and 3.989/1.413-11.26,p=0.009),rs2736098 in TERT(recessive model,OR/95%CI: 2.322/1.028-5.242.p=0.042)and rs62054619 in GAS8-AS1(recessive model,OR/95%CI: 2.219/1.067-4.617,p=0.033)were associated with the risk for PTC.rs1137282 in KRAS(dominant model,OR/95%CI:0.5430/0.3192-0.9236,p=0.024),rs1347591 and rs4461062 in NUP93(dominant model,OR/95%CI: 0.6121/0.4128-0.9076,p=0.015 and 0.6156/0.4157-0.9117,p=0.015)were found associated with low risk of distant metastatic disease in PTC patients.rs33954691 in TERT was found associated with risk of radioiodine-refractory PTC under dominant model(OR/95%CI:3.161/1.596-6.262).Conclusions Germline variants of related genes are associated with the susceptibility of papillary thyroid cancer as well as disease progression(distant metastasis and radioiodine-refractory status).Our findings could contribute to better understanding of thyroid cancer tumorigenesis/development and provide new strategies to better management of these patients.However,the results must be further verified and the potential biological functions of these germline variants in the pathogenesis of PTC remain to be determined in future studies. |
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