BRAF基因突變在甲狀腺乳頭狀癌中應(yīng)用

1、BRAF基因突變在甲狀腺乳頭狀癌中應(yīng)用*目錄 CONTENTS相關(guān)文獻(xiàn)回顧相關(guān)文獻(xiàn)回顧BRAF基因基因BRAF與與PTC展望展望* 相關(guān)相關(guān)文獻(xiàn)回顧文獻(xiàn)回顧1* BRAF文獻(xiàn)回顧BRAF Mutations in Hairy-Cell Leukemia The BRAF V600E mutation was present in all patients with HCL who were evaluated Implications for the pathogenesis, diagnosis, and targeted therapyN Engl J Med June 16 2011;3

2、64:2305-15.；毛細(xì)胞白血病毛細(xì)胞白血病所有毛細(xì)胞白血病BRAF V600E發(fā)生了變異可以用來研究發(fā)病機(jī)理、診斷、靶向治療* BRAF文獻(xiàn)回顧C(jī)etuximab and Chemotherapy as Initial Treatment for Metastatic Colorectal CancerCetuximab plus FOLFIRI compared with FOLFIRI alone reduced the risk of progression of metastatic colorectal cancerN Engl J Med april 2,2009;360:1

3、408-17.轉(zhuǎn)移性結(jié)直腸癌西妥昔單抗合并 FOLFIRI 降低對KRAS突變轉(zhuǎn)移性結(jié)直腸癌患者的疾病進(jìn)展風(fēng)險2011版NCCN提出：具有BRAF突變的患者預(yù)后差，一線治療后疾病進(jìn)展的，利用西妥昔單抗治療是無效的* BRAF文獻(xiàn)回顧Improved Survival With Vemurafenib In Melanoma With BRAF V600E MutationAberrant activation of the BRAF kinase occurs in 60% of melanomas, and although BRAF inhibitors have shown signif

4、icant early clinical successN Engl J Med 2011;364:2507-16.黑色素瘤在黑色素瘤中有60%患者發(fā)生BRAF V600E突變發(fā)生BRAF V600E突變的患者經(jīng)vemurafenib（威羅菲尼）治療，患者的總生存率和無進(jìn)展生存率分別提高（37%&26%）。但易產(chǎn)生耐藥。* BRAF基因介紹基因介紹2* PTC中中BRAF基因突變的分布基因突變的分布The worldwide prevalence of BRAF mutations in PTCEndocrine-Related Cancer (2006) 13 455464 文獻(xiàn)結(jié)論

5、 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 tumor

6、s.The B-RAFV600E was correlated with an older age at diagnosis (P =0.01) Endocrine-Related Cancer (2006) 13 455464 BRAF基因突變的致病機(jī)理基因突變的致病機(jī)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 increa

7、sing 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信號通路信號通路Expert Rev. Mol. Diagn. Future Science Group (2012)BRAF蛋白與KRAS蛋白同為 RAS-RAF-MEK-ERK信號通 路中上游調(diào)節(jié)因子，在 MAPK/ERK信號通路中起著 舉足輕重的作用；通

8、過這些途徑，將胞外信號轉(zhuǎn)化為胞內(nèi)信號，從而有效 應(yīng)對外界的信號刺激，調(diào)節(jié)細(xì)胞的生長、增殖、分化， 抑制細(xì)胞的凋亡。Ad PRASBRAFMEKERKERKNucleusNuclear gene regulationFigure 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 ser

9、ies 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:

10、Receptor tyrosine kinase.Ad P MAPK通路通路Activation of MAPK signaling pathway by RAS, RET/PTC and BRAFV600E mutations.J Chin Med Assoc March 2010 Vol 73 No 3 MAPK通路負(fù)反饋通路負(fù)反饋J Chin Med Assoc March 2010 Vol 73 No 3Proposed model of feedback inhibition in tumor cells with RET/PTC or RTKs and with BRAFV600E

11、* BRAF與與PTC3* BRAF基因突變的臨床應(yīng)用協(xié)助診斷協(xié)助診斷判斷預(yù)后判斷預(yù)后指導(dǎo)治療指導(dǎo)治療PTCBRAF突變突變*BRAF基因突變在FNAB中的應(yīng)用文獻(xiàn)文獻(xiàn) The role of BRAFV600E mutation and ultrasonography for the surgical management of a thyroid nodule suspicious for papillary thyroid carcinoma on cytology Moon HJ, Yonsei University College of Medicine, Seoul, South

12、Korea.Ann Surg Oncol. 2009 Nov;16(11):3125-31術(shù)前診斷術(shù)前診斷91例通過FNAB懷疑PTC，42例發(fā)生BRAFV600E變異，術(shù)后組織病理全部是PTC，準(zhǔn)確率100%。BRAFV600E陰性，術(shù)前診斷依賴于B超，術(shù)后：組織病理BRAF基因突變與臨床病理特征分析32個研究6372個患者2個前瞻性2個常規(guī)行CND淋巴結(jié)轉(zhuǎn)移臨床分期甲狀腺外侵犯腫瘤大小性別年齡多發(fā)病灶有無包膜亞型血管侵犯年齡與血管侵犯無統(tǒng)計學(xué)意義 BRAF基因突變預(yù)測DFSBRAF基因突變陽性患者更可能（ OR，3.06; 95CI，1.10-8.47， P=.032）產(chǎn)生PTC的持久性/

13、復(fù)發(fā)。通過細(xì)針穿刺細(xì)胞學(xué)標(biāo)本檢測BRAF 突變狀態(tài)，對PTC的持久性/復(fù)發(fā)的 評估具有重要的預(yù)后價值。Xing M. et al.J Clin Oncol JUNE 20 200927:2977-2982.對FNA不能確診的患者的治療策略對于細(xì)胞學(xué)診斷不確定的細(xì)針穿刺樣本進(jìn)行BRAF分析BRAF V600E呈陰性（如果該患者沒有其他風(fēng)險因素）BRAF V600E呈陽性患者6-12月后再次接受穿刺檢查全甲狀腺切除+中央淋巴清掃術(shù)Yale University：Adebowale J,et al. Reflex BRAF Testing in Thyroid Fine-Needle Aspirat

14、ionBiopsy with Equivocal and Positive Interpretation:A Prospective Study.Thyroid .2011.7(21):717-723*BRAF基因突變在CND中的應(yīng)用文獻(xiàn)文獻(xiàn) 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.Al

15、zahrani AS, Xing M Johns Hopkins University School of MedicineEndocr Relat Cancer. 2013 Jan 21;20(1):13-22指導(dǎo)指導(dǎo)CND379例甲狀腺全切除，243例行CND,136未行CND。CND從無、有限、正常。復(fù)發(fā)風(fēng)險率從4.7%、15.7%、40.5%（p0.0001)。CND從有限到正常，頸部淋巴結(jié)轉(zhuǎn)移率從18%到77.3%（p0.0001)。BRAFV600E變異有一致的結(jié)果。* 文文 獻(xiàn)獻(xiàn) 解解 讀讀4* JAMA 解 讀Association Between BRAFV600E Muta

16、tion and Mortality in Patients With Papillary Thyroid Cancer Objective：To investigate the relationship between BRAF V600E mutation and PTCrelated mortalityMingzhao Xing, MD, PhD， Division of Endocrinology and Metabolism, JohnsHopkins University Schoolof MedicineJAMA, April 10, 2013Vol 309, No. 14背景背

17、景回顧性研究 多中心1849例患者（男性 438，女性 1411）7個國家，13個中心 ，時間跨度（1978-2011）中位年齡46歲 （34-58）中位隨訪時間 33月 （13-67月）* 研 究 概 況 入入 組組 標(biāo)標(biāo) 準(zhǔn)準(zhǔn)所有病例為PTC，甲狀腺全切除治療性NLD按標(biāo)準(zhǔn)適應(yīng)癥病理診斷符合WHO標(biāo)準(zhǔn)術(shù)后按治療標(biāo)準(zhǔn)行I131治療隨訪起點(diǎn)：第一次手術(shù)后死亡標(biāo)準(zhǔn)：死于PTC，排除其他死因結(jié) 果總死亡率：5.3%(45/845） vs 1.1% (11/1004）(P .001)千人年死亡率：12.87 vs 2.52千人年死亡率（傳統(tǒng)PTC）： 11.80vs 2.25 風(fēng)險率（HR)：2.6

18、6 不同研究中心死亡相關(guān)分析BRAF總突變45.7%總死亡：56人 占3%其中 45人BRAF基因突變 占80.4%總死亡：BRAF（+）5.3%BRAF（-）1.1% 不同病理類型死亡相關(guān)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 年齡及臨床特征死亡相關(guān)分析有明顯統(tǒng)計學(xué)意義:年齡大于45歲

19、尤其大于60歲無明顯統(tǒng)計學(xué)意義：無淋巴結(jié)轉(zhuǎn)移無遠(yuǎn)處轉(zhuǎn)移甲狀腺外侵犯StageI、II、III腫瘤大小 Kaplan-Meier 生存曲線生存曲線Kaplan-Meier 生存曲線分層生存曲線分層Kaplan-Meier 生存曲線生存曲線 年齡年齡 結(jié)結(jié) 論論 BRAFV600E基因突變與PTC總死亡率明顯相關(guān)（80.4%） BRAFV600E基因突變不是PTC死亡率預(yù)測的獨(dú)立因子，但給研究其分子機(jī)理及其他基因提供了依據(jù)（VEGF、c-MET等），更有利于分層研究 為PTC的預(yù)后判斷及治療提供了一定的依據(jù) 鑒于PTC總體生存期長，隨訪時間短,其死亡率相關(guān)性的原因尚不清楚，有待進(jìn)一步研究* NEJM 解 讀Preoperative Diagnosis of Benign Thyroid Nodules with Indeterminate Cytology Objective： A novel diagnostic test improve the preoperative risk assessment for Patients with cytologically indeterminate n