The Effect Of BRAF V600E And TERT Promoter Mutations In Patients With Papillary Thyroid Carcinoma Postoperative After RAI Therapy

Objective:1.Observe the status of BRAF V600 E and TERT promoter mutations in PTC postoperative,and analyze the basic situation of two kinds of mutations in Chinese patients.2.Observe the status of BRAF V600 E and TERT promoter mutations in patients with PTC distant metastases.Evaluate the effects of RAI therapy and the value of radionuclide therapy(Tg,whole-body scan,¹⁸F-FDG,etc.).3.Tg was the specific tumor marker after total resection of PTC.?Tg/?TSH could predict recurrence and metastasis.Observe the status of BRAF V600 E and TERT promoter mutations in patients with PTC distant metastases.Evaluate the determine efficiency of ?Tg/?TSH.Methods:1.A total of 87 patients with thyroid papillary carcinoma?PTC?who underwent surgery from January 2015 to February 2015 in China-Japanese Hospital of Jilin University were selected.All patients had complete datas of the case and the paraffinembedded tissue,extract the genomic DNA of tumor tissue.The BRAF V600 E mutation was detected by fluorescence PCR.The TERT promoter mutation was detected by standard PCR and sequencing techniques.Compared with the difference of BRAF V600 E genotype distribution,TERT promoter genotype distribution ratio,and the difference of the sex,age,tumor size,extravial invasion and other clinical pathological parameters with two mutations in different mutations state.2.A total of 64 patients with PTC patients who underwent at least two courses of RAI therapy after total thyroidectomy from May 2012 to September 2014 in ChinaJapanese Hospital of Jilin University were selected.The methods of gene detection as above.All patients underwent ¹⁸F-FDG PET/CT imaging within one week prior tothe first RAI therapy and the whole-body scan?Rx WBS?were performed 5 days after RAI therapy.The results of imaging with semi-quantitative analysis and the T/NT ratios and SUVmax were obtained.Before the first and second IV treatment to detect Tg levels.According to the imaging and pathological data to decide the value of RAI therapy during the follow-up period.According to the corresponding guidelines,all patients were divided into complete remission group,incomplete remission group and progressive group.Analysis the T/NT ratio,the SUVmax value,the Tg level,the Tg variation??Tg?and the rate of Tg with distant metastases in different mutations retrospectively.3.A total of 431 patients with PTC who underwent RAI therapy after total thyroidectomy from January 2015 to September 2016 in the department of Nuclear Medicine in China-Japanese Hospital of Jilin University were enrolled.According to the imaging examination?chest CT,cervical ultrasonography,whole body bone imaging,Dx WBS,Rx WBS?,examined the pathology to patients with suspected metastatic.According to the results,the patients were divided into two groups: no distant metastasis group?M0 group,n=378 cases?and distant metastasis group?M1group,n=53 cases?.BRAF V600 E and TERT promoter mutations were analyzed in the M1 group.After surgery for the 14 th day,the 21 st day and the 28 th day to detect the level of Tg and TSH.The results were defined as Tg1,TSH1,Tg2,TSH2,Tg3,TSH3.Compare with the variation tendency of Tg,?Tg and ?Tg/?TSH ratio between these three groups.The receiver operating characteristic?ROC?curves and diagnostic critical point?DCP?were employed to evaluate the predictive value of the above indicators for distant metastasis.According to the difference of the status of mutations,the M1 group was divided into different subgroups.Compare the variation tendency of Tg,?Tg and ?Tg/?TSH ratio between the M1 subgroups.The receiver operating characteristic?ROC?curves and diagnostic critical point?DCP?were employed to evaluate the predictive value of the above indicators for distant metastasis.Results:1.The prevalence of BRAF V600 E mutations was 74.7%?65/87?,and the prevalence of TERT promoter mutations was 6.9%?6/87?.We took the advantage of the cases to analyze the relationship of BRAF V600 E mutation with clinicopathological characteristics of PTC.There is association of BRAF V600 E mutation with adenocarcinoma,vascular invasion,lymph node metastasis and stageIV,and the difference was statistically significant?P<0.05?.TERT promoter mutation in addition to the extrahepatic invasion,vascular invasion,lymph node metastasis and stage IV,it was related to the size and distant metastasis,and the difference was statistically significant?P<0.05?.The BRAF V600 E mutation and TERT promoter mutation were divided into four subgroups.Compared with the double negative group,only the BRAF V600 E mutation was related to adenocarcinoma,lymph node metastasis and pathological stage III + IV,and the difference was statistically significant?P<0.05?.The presence of TERT promoter mutation was only related to lymph node metastasis?P<0.05?.The BRAF V600 E and TERT promoter mutations were associated with tumor size,extravasation,invasion,lymph node metastasis,stage IV and distant metastasis,the difference was statistically significant?P<0.05?.2.The prevalence of BRAF V600 E mutation was 75%?48/64?in distant metastasis patients,and the prevalence of TERT promoter mutation was 26.6%?18/64?in distant metastasis patients.We took the advantage of the cases to analyze the relationship of BRAF V600 E mutation with clinicopathological characteristics of PTC.There is association of BRAF V600 E mutation with adenocarcinoma,vascular invasion,lymph node metastasis,and the difference was statistically significant?P<0.05?.TERT promoter mutation in addition to the extrahepatic invasion,vascular invasion,lymph node metastasis,it was related to the size,and the difference was statistically significant?P<0.05?.The BRAF V600 E mutation and TERT promoter mutation were divided into four subgroups.Compared with the double negative group,only the BRAF V600 E mutation was only related to adenocarcinoma,lymph node metastasis,and the difference was statistically significant?P<0.05?.The presence of TERT promoter mutation was related to tumor size and lymph node metastasis?P<0.05?.The BRAF V600 E and TERT promoter mutations were associated with tumor size,extravasation,invasion,lymph node metastasis,the difference was statistically significant?P<0.05?.64 patients with distant metastasis of the prevalence of BRAF V600 E and TERT promoter mutations compared with the first part of the overall prevalence of patients,BRAF V600 E and TERT promoter mutations?P=0.033?,only the TERT promoter mutation and the TERT promoter mutant?P=0.002?were significantly difference,respectively.The T/NT ratio of different genotypes after¹³¹I treatment and the second ¹³¹I treatment showed that both the BRAF V600 E mutant and the TERT promoter mutant had lower T/NT ratios compared with the wildtype?P<0.05?.When the BRAF V600 E and TERT promoter mutations coexist,the T/NT ratio was significantly lower than that of the BRAF V600 E mutation alone?P<0.05?.The change of SUVmax value of different genotypes before ¹³¹I treatment showed that the SUVmax value of TERT promoter mutation was higher than that of wild type?P<0.05?.The results showed that the Tg,?Tg,and the rate of Tg predicte progressive disease the cut-off value of the rate of Tg,which was more in predicting distant metastasis was 25% with a sensitivity of 90.0%,and a specificity of 96.7%,and a accuracy of 94.6%,the corresponding area under the ROC curve was 0.946.The results showed that the Tg,?Tg,and the rate of Tg predicte complete remission the cut-off value of the rate of Tg,which was more in predicting distant metastasis was-22% with a sensitivity of 91.8%,and a specificity of 100%,and a accuracy of 93.7%,the corresponding area under the ROC curve was 0.990.3.431 patients of PTC,there were no significant differences in age,sex,TSH1 and TSH2 between the M0 and M1 groups?P>0.05?,Tg1,Tg2,Tg3,TSH3,?Tg1,?Tg2,?Tg3,?Tg1/?TSH1,?Tg2/?TSH2,?Tg3/?TSH3 were statistically significant,P<0.05.Between the two groups of serum markers to predict the value of distant metastasis before ¹³¹I treatment,the cut-off value of ?Tg3/?TSH3,which was more in predicting distant metastasis was 0.51 with a sensitivity of 96.2%,and a specificity of 98.9%,and a accuracy of 98.6%,the corresponding area under the ROC curve was 0.990.The value of distant metastasis in different mutation before and after¹³¹I treatment showed that ?Tg3/?TSH3 in the double negative group,the cut-off value was more in predicting distant metastasis was 0.51 with a sensitivity,specificity and accuracy were 100%,the corresponding area under the ROC curve was 1.Only BRAF V600 E mutation group,the cut-off value of ?Tg3/?TSH3 was more in predicting distant metastasis was 0.52 with a sensitivity of 94.7%,and a specificity of93.6%,and a accuracy of 93.8%,the corresponding area under the ROC curve was0.986.Only the TERT promoter mutation group,the cut-off value of ?Tg3/?TSH3was more in predicting distant metastasis was 1.19 with a sensitivity,specificity and accuracy were 100%,the corresponding area under the ROC curve was 1.BRAF V600 E and TERT promoter mutations group,the cut-off value of ?Tg3/?TSH3 was more in predicting distant metastasis was 1.38 with a sensitivity,specificity and accuracy were 100%,the corresponding area under the ROC curve was 1.Conclusion:BRAF V600 E mutation and TERT promoter mutation cooperatively in patients with PTC,the risk of metastasis is higher,and the metastatic foci associated with nonRAI-avid status.In this time,Tg level can not determine whether there is metastasis.Therefore,the effect of¹³¹I treatment is poor,and more easily metastasis.This patients should be early intervention.