BRAF基因突变在甲状腺乳头状癌中的应用

1、1会计学BRAF基因突变在甲状腺乳头状癌中的应基因突变在甲状腺乳头状癌中的应用用*相关文献回顾BRAF基因BRAF与PTC文献精选展望*1*BRAF Mutations in Hairy-Cell Leukemian The BRAF V600E mutation was present in all patients with HCL who were evaluatedn Implications for the pathogenesis, diagnosis, and targeted therapynN Engl J Med June 16 2011;364:2305-15.；毛细胞白

2、血病毛细胞白血病n所有毛细胞白血病BRAF V600E发生了变异n可以用来研究发病机理、诊断、靶向治疗*Cetuximab and Chemotherapy as Initial Treatment for Metastatic Colorectal CancernCetuximab plus FOLFIRI compared with FOLFIRI alone reduced the risk of progression of metastatic colorectal cancerN nEngl J Med april 2,2009;360:1408-17.转移性结直肠癌n西妥昔单抗合

3、并 FOLFIRI 降低对KRAS突变转移性结直肠癌患者的疾病进展风险n2011版NCCN提出：具有BRAF突变的患者预后差，一线治疗后疾病进展的，利用西妥昔单抗治疗是无效的*Improved Survival With Vemurafenib In Melanoma With BRAF V600E MutationnAberrant activation of the BRAF kinase occurs in 60% of melanomas, and although BRAF inhibitors have shown significant early clinical succes

4、snN Engl J Med 2011;364:2507-16.黑色素瘤n在黑色素瘤中有60%患者发生BRAF V600E突变n发生BRAF V600E突变的患者经vemurafenib（威罗菲尼）治疗，患者的总生存率和无进展生存率分别提高（37%&26%）。但易产生耐药。*2*The worldwide prevalence of BRAF mutations in PTCEndocrine-Related Cancer (2006) 13 455464The model illustrates the two major signaling pathways, the PI3K/A

5、kt 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. Futur

6、e 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 PRASBRAFMEKERKERKNucleusNuclear gene regulationFigure 1. Molecular signaling of the MAP kinase pathway. RTK dimerizes uponligand (growth factor, cy

7、tokine 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 tr

8、anslocates from cytosol into nucleus to regulate gene expression.Ad P: Adaptor protein; RTK: Receptor tyrosine kinase.Ad PActivation of MAPK signaling pathway by RAS, RET/PTC and BRAFV600E mutations.J Chin Med Assoc March 2010 Vol 73 No 3J Chin Med Assoc March 2010 Vol 73 No 3Proposed model of feedb

9、ack inhibition in tumor cells with RET/PTC or RTKs and with BRAFV600E*3*协助诊断判断预后指导治疗PTCBRAF突变*文献n The role of BRAFV600E mutation and ultrasonography for the surgical management of a thyroid nodule suspicious for papillary thyroid carcinoma on cytology nMoon HJ, Yonsei University College of Medicine,

10、 Seoul, South Korea.nAnn Surg Oncol. 2009 Nov;16(11):3125-31术前诊断术前诊断n91例通过FNAB怀疑PTC，42例发生BRAFV600E变异，术后组织病理全部是PTC，准确率100%。nBRAFV600E阴性，术前诊断依赖于B超，术后：组织病理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

11、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.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

12、Prospective Study.Thyroid .2011.7(21):717-723*文献n Impact of lymph node metastases identified on central neck dissection (CND) on the recurrence of papillary thyroid cancer: potential role of BRAFV600E mutation in defining CND.nAlzahrani AS, Xing M Johns Hopkins University School of MedicinenEndocr R

13、elat Cancer. 2013 Jan 21;20(1):13-22指导指导CNDn379例甲状腺全切除，243例行CND,136未行CND。CND从无、有限、正常。复发风险率从4.7%、15.7%、40.5%（p0.0001)。nCND从有限到正常，颈部淋巴结转移率从18%到77.3%（p0.0001)。nBRAFV600E变异有一致的结果。*4*Association Between BRAFV600E Mutation and Mortality in Patients With Papillary Thyroid Cancern Objective：To investigate t

14、he relationship between BRAF V600E mutation and PTCrelated mortalitynMingzhao Xing, MD, PhD， Division of Endocrinology and Metabolism, JohnsHopkins University Schoolof MedicinenJAMA, April 10, 2013Vol 309, No. 14背景背景n回顾性研究 多中心n1849例患者（男性 438，女性 1411）n7个国家，13个中心 ，时间跨度（1978-2011）n中位年龄46岁 （34-58）n中位随访时

15、间 33月 （13-67月）* 入入 组组 标标 准准n所有病例为PTC，甲状腺全切除n治疗性NLD按标准适应症n病理诊断符合WHO标准n术后按治疗标准行I131治疗n随访起点：第一次手术后n死亡标准：死于PTC，排除其他死因结 果n总死亡率：5.3%(45/845） vs 1.1% (11/1004）(P .001)n千人年死亡率：12.87 vs 2.52n千人年死亡率（传统PTC）： 11.80vs 2.25 n风险率（HR)：2.66 *Preoperative Diagnosis of Benign Thyroid Nodules with Indeterminate Cytolog

16、yn Objective： A novel diagnostic test improve the preoperative risk assessment for Patients with cytologically indeterminate nodulesnErik K et.al， Harvard Medical School,University of Washington School of Medi-cine,Johns Hopkins University School of Medicine et.al.eight UniversitynN Engl J Med June

17、25, 2012 nDOI: 10.1056/NEJMoa1203208背景背景n前瞻性研究 多中心 双盲 历时19月 随访301天n3789例患者,4812个结节，直径大于1cmn美国8所大学，49个中心，577例细胞学不能确定，265例行基因测定* 入入 组组 标标 准准nB超引导（99%）细针穿刺，组织病理确认并有基因检测结果n细胞学病理评价：两名病理医生确认，有争议的需第三名病理医生确认n细针穿刺取材2-5次n最终入选265例结 果n恶性85例，基因确认78例，敏感性92%n良性180例，基因确认93例，特异性52%n异形细胞、滤泡状肿瘤、怀疑恶性的敏感性分别为90%、90%、94%。

18、阴性预测价值分别为95%、94%、85%。*5Thanks！*BRAF Mutations in Hairy-Cell Leukemian The BRAF V600E mutation was present in all patients with HCL who were evaluatedn Implications for the pathogenesis, diagnosis, and targeted therapynN Engl J Med June 16 2011;364:2305-15.；毛细胞白血病毛细胞白血病n所有毛细胞白血病BRAF V600E发生了变异n可以用来研究发病机理、诊断、靶向治疗*2 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