BRAF V600E和PD-L1蛋白表达在甲状腺乳头状癌中的临床意义

Clinical significance of BRAFV600E and PD-L1 protein expression in papillary thyroid carcinoma

摘要:

目的：研究甲状腺乳头状癌（papillary thyroid carcinoma，PTC）中BRAF V600E与程序性死亡因子配体1（programmed death ligand 1，PD-L1）蛋白表达，探讨其与PTC临床特征的相关性。方法：随机收集2015至2017年重庆医科大学附属第一医院128例PTC患者作为研究对象，收集40例甲状腺癌旁正常组织患者作为对照。采用免疫组化检查BRAF V600E蛋白和PD-L1蛋白的表达。结果：PTC中BRAF V600E蛋白阳性率为67.9%（87/128），明显高于正常组（ ?字2=11.693，P=0.000）；单因素卡方检验分析BRAF蛋白阳性与患者年龄≥45岁（ ?字2=22.345，P=0.000）、甲状腺包膜侵犯（ ?字2=4.643，P=0.031）关系密切。而PD-L1在PTC中阳性率为57.8%（74/128），明显高于正常组织（ ?字2=9.812，P=0.000）；单因素卡方检验分析PD-L1蛋白阳性与PTC患者年龄≥45岁（ ?字2=44.390，P=0.000）、淋巴结转移状态（ ?字2=28.584，P=0.000）及甲状腺包膜侵犯（ ?字2=12.895，P=0.000）显著相关。多因素logistic回归分析显示BRAF蛋白的表达与患者患者年龄≥45岁（OR=3.003，95%CI=1.218~7.404，P=0.017）、甲状腺包膜侵犯（OR=12.341，95%CI=3.944~38.620，P=0.000）关系密切，PD-L1蛋白表达与患者患者年龄≥45岁（OR=6.667，95%CI=2.668~16.657，P=0.000）、淋巴结转移（OR=3.987，95%CI=1.592~9.987，P=0.003）和甲状腺包膜侵犯（OR=4.249，95%CI=1.447~12.478，P=0.008）关系密切。进一步分析显示，BARFV600E蛋白阳性的PTC中PD-L1阳性率为75.8%（66/87），明显高于BARF蛋白阴性PTC中PD-L1阳性率19.5%（8/41）（Kappa=0.520，P=0.000）。提示在甲状腺乳头状癌中，BRAF蛋白与PD-L1蛋白表达存在一致性。结论：BRAF蛋白阳性的PTC中，PD-L1免疫抑制分子存在过量表达，BRAFV600E蛋白和PD-L1蛋白的共同过量表达与患者更差的预后相关。

Abstract:

Objective：To detect the expression of BRAF V600E and PD-L1 in papillary thyroid carcinoma（PTC） and to explore its correlation with clinical features of PTC. Methods：Totally 128 cases of PTC in the First Affiliated Hospital of Chongqing Medical University from the year 2015 to 2017 were randomly collected as the research subjects，and 40 cases of normal thyroid tissue were served as controls. The expression of BRAF V600E and PD-L1 protein was detected using immunohistochemistry. Results：The positive rate of BRAF V600E protein was 67.9%（87/128） in PTC，which was significantly higher than that in normal thyroid tissue（ ?字2=11.693，P=0.000），and it was closely related to the age of patients [more than or equal to 45 years old（ ?字2=22.345，P=0.000）] and thy－roid capsule invasion（ ?字2=4.643，P=0.031）. The positive rate of PD-L1 protein was 57.8%（74/128） in PTC，which was also signifi－cantly higher than that in normal thyroid tissue（ ?字2=9.812，P=0.000），and it was significantly correlated with the age[more than or equal to 45 years old， ?字2=44.390，P=0.000）]，lymph node metastasis（ ?字2=28.584，P=0.000） and thyroid capsule invasion（ ?字2=12.895，P=0.000）. Multiple factors analysis showed that BRAF V600E protein expression was significantly correlated with age≥45（OR=3.003，95%CI=1.218 to 7.404，P=0.017） and thyroid capsule in－vasion（OR=12.341，95%CI=3.944 to 38.620，P=0.000）. PD-L1 protein expression was significantly correlated with age≥45（OR=6.667，95%CI=2.668 to 16.657，P=0.000），lymph node metastasis（OR=3.987，95%CI=1.592 to 9.987，P=0.003） and thyroid capsule invasion（OR=4.249，95%CI=1.447 to 12.478，P=0.008）. Further analysis showed that the PD-L1 expression rate in the PTC patients with positive BARF V600E expression was 75.8%（66/87），which was significantly higher than that in the PTC patients with negative BARF V600E expression 19.5%（8/41）（?资=0.520，P=0.000）. There was a consistency between BRAF protein and PD-L1 protein expression in thyroid papillary carcinoma. Conclusion：This study show immunosuppressive molecule PD-L1 is overexpressed in the PTC patients with positive BARF V600E expression，and the co-overexpression of BRAF V600E and PD-L1 protein in PTC patients is associated with the worse prognosis.