BRAF基因突变在甲状腺乳头状癌中的应用

李永平Doctor Li,BRAF基因突变在甲状腺乳头状癌中的临床应用,2014-04-23,*,目录 CONTENTS,*,相关文献回顾,1,*,BRAF文献回顾,*,BRAF文献回顾,*,BRAF文献回顾,*,BRAF基因介绍,2,*,PTC中BRAF基因突变的分布,The worldwide prevalence of BRAF mutations in PTC,Endocrine-Related Cancer (2006) 13 455464,文献结论, B-RAFV600E mutation was found in 99 out of 260 PTCs (38%) The B-RAFV600E mutation was present in 48.3% of cases of classic PTC (85 out of 176), in 17.6% (nine out of 51) of follicular variants of PTC, in 21.7% (five out of 23) of other PTC variants and in none of the ten poorly differentiated tumors.The B-RAFV600E was correlated with an older age at diagnosis (P =0.01) Endocrine-Related Cancer (2006) 13 455464,BRAF基因突变的致病机理,The model illustrates the two major signaling pathways, the PI3K/Akt and the MAP kinase pathways。The increasing color intensity of the circle represents the increasing progression and aggressiveness ofthe tumor. MAPK pathway, the RasRafMEKMAPERK pathway.,Clin Cancer Res 2007;13:1161-1170.,Peng Hou, Dingxie Liu, Yuan Shan, et al.,BRAF信号通路,Expert Rev. Mol. Diagn. Future Science Group (2012),BRAF蛋白与KRAS蛋白同为 RAS-RAF-MEK-ERK信号通 路中上游调节因子，在 MAPK/ERK信号通路中起着 举足轻重的作用；通过这些途径，将胞外信号转化为胞内信号，从而有效 应对外界的信号刺激，调节细胞的生长、增殖、分化， 抑制细胞的凋亡。,Ad P,RAS,BRAF,MEK,ERK,ERK,Nucleus,Nuclear gene regulation,Figure 1. Molecular signaling of the MAP kinase pathway. RTK dimerizes uponligand (growth factor, cytokine and hormone) binding and acquires ikinasedomain,leading to activation of RAS via a series of Ad Ps. Through cascadephosphorylation events, the activated RAS recruits BRAF to the cell membrane andactivates it. BRAF then activates downstream MEK, which in turn activates ERK. Theactivated ERK translocates from cytosol into nucleus to regulate gene expression.Ad P: Adaptor protein; RTK: Receptor tyrosine kinase.,Ad P,MAPK通路,Activation of MAPK signaling pathway by RAS, RET/PTC and BRAFV600E mutations.,J Chin Med Assoc March 2010 Vol 73 No 3,MAPK通路负反馈,J Chin Med Assoc March 2010 Vol 73 No 3,Proposed model of feedback inhibition in tumor cells with RET/PTC or RTKs and with BRAFV600E,*,BRAF与PTC,3,*,BRAF基因突变的临床应用,协助诊断,判断预后,指导治疗,PTC,BRAF突变,*,BRAF基因突变在FNAB中的应用,BRAF基因突变与临床病理特征分析,32个研究6372个患者2个前瞻性2个常规行CND淋巴结转移临床分期甲状腺外侵犯肿瘤大小性别年龄多发病灶有无包膜亚型血管侵犯年龄与血管侵犯无统计学意义,BRAF基因突变预测DFS,BRAF基因突变阳性患者更可能（ OR，3.06; 95CI，1.10-8.47， P=.032）产生PTC的持久性/复发。,通过细针穿刺细胞学标本检测BRAF 突变状态，对PTC的持久性/复发的 评估具有重要的预后价值。,Xing M. et al.J Clin Oncol JUNE 20 200927:2977-2982.,对FNA不能确诊的患者的治疗策略,对于细胞学诊断不确定的细针穿刺样本进行BRAF分析,BRAF V600E呈阴性（如果该患者没有其他风险因素）,BRAF V600E呈阳性患者,6-12月后再次接受穿刺检查,全甲状腺切除+中央淋巴清扫术,Yale University：Adebowale J,et al. Reflex BRAF Testing in Thyroid Fine-Needle AspirationBiopsy with Equivocal and Positive Interpretation:A Prospective Study.Thyroid .2011.7(21):717-723,*,BRAF基因突变在CND中的应用,*,文 献 解 读,4,*,JAMA 解 读,*,研 究 概 况,不同研究中心死亡相关分析,BRAF总突变45.7%总死亡：56人 占3%其中 45人BRAF基因突变 占80.4%总死亡：BRAF（+）5.3%BRAF（-）1.1%,不同病理类型死亡相关分析,All types ： 56/1849 (3.0) 45/845 (5.3) 11/1004 (1.1) .001Conventional ： 39/1233 (3.2) 33/659 (5.0) 6/574 (1.0) .001Follicular variant： 6/411 (1.5) 4/82 (4.9) 2/329 (0.6) .02,年龄及临床特征死亡相关分析,有明显统计学意义:年龄大于45岁尤其大于60岁无明显统计学意义：无淋巴结转移无远处转移甲状腺外侵犯StageI、II、III肿瘤大小,Kaplan-Meier 生存曲线,Kaplan-Meier 生存曲线分层,Kaplan-Meier 生存曲线 年龄,结 论, BRAFV600E基因突变与PTC总死亡率明显相关（80.4%） BRAFV600E基因突变不是PTC死亡率预测的独立因子，但给研究其分子机理及其他基因提供了依据（VEGF、c-MET等），更有利于分层研究 为PTC的预后判断及治疗提供了一定的依据 鉴于PTC总体生存期长，随访时间短,其死亡率相关性的原因尚不清楚，有待进一步研究,*,NEJM 解 读,*,研 究 概 况,结 论, 在FNBA-PTC中，如果细胞病理学不能确定，BRAFV600E基因表达分类预测良性的价值大于恶性 仍有15%的甲状腺癌不能为全切除或不全切除提供依据 基因表达细胞学区分良、恶性敏感性为100%，良性特异性为70%，故不能用于测定良性病变 为细