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Advances in Clinical Medicine
Vol. 12  No. 09 ( 2022 ), Article ID: 55935 , 9 pages
10.12677/ACM.2022.1291227

BRAF V600E在甲状腺乳头状癌临床应用性中的研究进展

刘延泽1*，刘嘉琦2，李良2#

1滨州医学院，山东 滨州

2滨州医学院附属淄博市中心医院，山东 淄博

收稿日期：2022年8月15日；录用日期：2022年9月9日；发布日期：2022年9月19日

摘要

甲状腺癌发病率在近几十年间呈增长趋势，乳头状癌是其最常见的组织学分型。BRAF V600E突变基因已成为甲状腺乳头状癌已知的重要驱动基因，在疾病诊断、病情评估、治疗策略、预后判断等方面起重要作用。本文对BRAF V600E在以上四个方面中的应用进展进行综述。

关键词

BRAF V600E，甲状腺乳头状癌，综述

Research Progress of BRAF V600E Gene Mutation in Papillary Thyroid Carcinoma

Yanze Liu1*, Jiaqi Liu2, Liang Li2#

1Binzhou Medical University, Binzhou Shandong

2Zibo Center Hospital Affiliated to Binzhou Medical University, Zibo Shandong

Received: Aug. 15th, 2022; accepted: Sep. 9th, 2022; published: Sep. 19th, 2022

ABSTRACT

The incidence of thyroid carcinoma has been increasing in recent decades, and papillary carcinoma is the most common histological type. BRAF V600E mutation has become a known important driver gene of papillary thyroid carcinoma, which plays a significant role in disease diagnosis, disease evaluation, treatment strategy and prognosis evaluation. This paper reviews the application progress of BRAF V600E in the above four aspects.

Keywords:BRAF V600E, Papillary Thyroid Carcinoma, Review

Copyright © 2022 by author(s) and Hans Publishers Inc.

This work is licensed under the Creative Commons Attribution International License (CC BY 4.0).

http://creativecommons.org/licenses/by/4.0/

1. 引言

甲状腺癌(thyroid carcinoma, TC)是最常见的内分泌系统恶性肿瘤之一 [1] [2]，中国TC总人群标化发病率在1990到2019这29年间呈增长趋势，平均增长速度为2.67% [3]。TC分为分化型甲状腺癌(differentiated thyroid carcinoma, DTC)、甲状腺髓样癌和未分化型甲状腺癌，DTC包括甲状腺乳头状癌(papillary thyroid carcinoma, PTC)和甲状腺滤泡癌 [3] [4]。其中TC最常见的类型是甲状腺乳头状癌，占80%以上 [5]，其侵袭性较低，分化程度高，恶性程度低，患者10年生存率可达90% [6]。随着细针穿刺活检技术(fine-needle aspiration biopsy, FNAB)的普及，越来越多的PTC在早期被发现并治疗，但是FNAB过程中操作医生技术不佳或穿刺结节体积较小，可能会出现假阴性，BRAF基因检测联合超声引导下细针穿刺活检可提高PTC诊断率，降低穿刺结果中出现假阴性的可能性 [7] [8]。本文对BRAF V600E在PTC诊断、病情评估、治疗策略、预后判断四个方面发挥的作用作一综述。

2. BRAF V600E基因突变简介

BRAF(鼠类肉瘤滤过性毒菌致癌基因同源体)基因是一种原癌基因，它是TC发生发展过程中最常见的基因突变 [2] [9]，其定位于7q34 [10]。其对有丝分裂原活化蛋白增殖、分裂和存活过程中基因性状表达起转录调控作用，也在细胞骨架调动和细胞形态转换中起着关键作用 [11]。包括BRAF蛋白在内的丝氨酸–苏氨酸激酶，在MAPK/ERK信号传导级联中作为RAS的下游影响因子起不可或缺的作用 [12]，是下游MAPK信号转导途径的最强激活剂 [13]。BRAF活化错误点激酶结构域突变体一个集中在突变基因第11外显子，另一个集中在第15外显子上，后者上的转位突变(T1799A)在BRAF突变方式中占80%以上 [12]，它在BRAF基因的第1外显子中缺失了一个密码子，T1799A突变致使蛋白质产物中V599E氨基酸(如今命名为V600E)替换，在蛋白产物中表现为赖氨酸被谷氨酸所取代，随即BRAF激酶发生构成性激活 [12]。磷酸腺苷P环通常使BRAF处于非活性确认状态，BRAF V600E在激活的磷酸化位点Ser599附近插入一个负电荷残基，破坏磷酸腺苷P环与激活段的结合，导致BRAF转化为催化活性形式 [10]。突变后的BRAF基因致使下游MEK-ERK信号传导途径维持活化，引致细胞增殖不受控制、恶性细胞迁移、肿瘤组织血管生成和异常细胞逃避凋亡，在提升肿瘤侵袭性、肿瘤淋巴结转移、异型组织生长和增殖等方面起显著作用 [12] [14] [15]。自BRAF突变发现以来，它就在不同癌症当中被报道，如皮肤恶性黑色素瘤、甲状腺癌、结肠癌、恶性浆液性卵巢癌、非小细胞肺癌、朗格汉斯细胞组织细胞增多症(LCH)等 [12] [14] [15] [16] [17]。BRAF V600E的发现为提高甲状腺癌临床诊断率、优化治疗策略及方案创造了机会。

3. BRAF V600E与甲状腺乳头状癌诊断

3.1. BRAF V600E基因突变检测方法

检测BRAF基因突变的方法很多 [18]，测序法中的桑格(Sanger)测序法是当前临床医学界公认的检测BRAF最可靠的方法 [19]。近年来有研究表示：检测甲状腺癌BRAF基因突变应用二代测序(NGS)技术可获得与荧光定量PCR技术相当水平的临床结果，甚至可以检测出更多种的TC基因突变类型，有助于进一步认识TC的发生发展 [20]。另外有其他研究表示：检测PTC患者BRAF突变时应用微滴式数字PCR (droplet digital PCR, ddPCR)法检测肿瘤DNA占比小、突变相对含量低的样本，其具有检出成功率高和灵敏度高的特点，在临床检测中可以适当进行推广，以替代桑格(Sanger)测序法 [21]。针对晚期PTC患者可以利用cfDNA实现BRAF突变的快速检测，但其可靠程度低且价格昂贵，不适宜在临床上大规模推广使用 [22]。

3.2. BRAF V600E在甲状腺乳头状癌诊断中的作用

初次发现甲状腺结节，为方便临床医生进一步作出判断、给予相应的个体化治疗方案，应先行颈部高分辨率超声 [4]。对超声检查高度怀疑恶性征象的患者，推荐行超声引导下细针穿刺活检(ultrasound-guided fine-needle aspiration biopsy, US-FNAB) [4]。从目标病灶中获取组织成分，通过细胞学诊断判断结节性质。直径 < 5 mm的甲状腺结节，由于结节体积过小、医生穿刺技术等原因，穿刺结果可能存在假阴性，造成漏诊。相关研究表明，BRAF V600E基因检测联合FNAB能提高PTC诊断率，减少漏诊 [7] [8]，便于制订诊断和治疗治方案。

4. BRAF V600E与病情评估

4.1. BRAF V600E与淋巴结转移

虽然PTC预后良好，但是其拥有较高的颈部淋巴结转移(lymph node metastasis, LNM)率。LNM对术后的危险分层、治疗评估有重要的临床意义。LNM分为中央区淋巴结转移(central lymph node metastasis, CLNM)与侧颈淋巴结转移。相关研究表明，BRAF V600E表达促进了PTC淋巴结转移 [23]，伴有BRAF基因突变的单侧PTC患者发生CLNM的风险可能增加 [24] [25]。吴文年等对450例PTC患者进行研究，BRAF突变提高了侧颈LNM转移风险：BRAF基因突变组387例中有155例(40.1%)发生颈淋巴结转移；BRAF基因未突变组64例中有16例(25.4%)发生颈淋巴结转移 [26]。但有一部分研究显示，BRAF突变与LNM是否相关尚不清楚 [27] [28] [29]。因此，BRAF V600E与PTC淋巴结转移是否就有统计学意义还需进一步深入研究。另外，BRAF基因突变合并TERT启动子突变也与PTC侵袭性相关 [29]。

4.2. BRAF V600E与远处转移

PTC的远处转移(distant metastasis, DM)并不常见，但一旦发生，它会显著降低PTC患者的生存率。目前，对PTC中DM的分子机制尚未有系统的研究。Xiabin Lan、Alice L Tang、Ja Seong Bae及Huy Gia Vuong的研究团队对DM与PTC相关性进行研究，未发现BRAF与DM相关 [30] [31] [32] [33]。

5. BRAF V600E与治疗策略

5.1. BRAF V600E与手术方式

通常情况下，PTC患者需要手术治疗。BRAF V600E突变阳性是相对高危的PTC类型，其侵袭性及淋巴结转移率较野生型高 [11] [23] [34]，预后不良 [34] [35] [36]，患者身体条件允许手术的前提下，坚决选择手术 [4] [11]。

5.1.1. BRAF V600E与预防性颈部中央区淋巴结清扫

在相关研究表明，BRAF V600E突变基因阳性CLNM风险增加，建议行预防性颈中央区淋巴结清扫术(prophylactic central neck dissection, PCND) [37]。但也有研究表示，BRAF突变的存在对复发的阳性预测值(positive predictive value, PPV)有限，仅有28% [38] [39]。因此，B-RAF突变患者预防性颈部中央区淋巴结清扫的必要性需进一步探讨。

5.1.2. BRAF V600E与预防性侧颈区淋巴结清扫

B-RAF突变的患者行预防性侧颈区淋巴结清扫是否有必要？通常情况下对FNAB证实的以及高度怀疑PTC侧颈淋巴结转移者进行治疗性侧颈淋巴结清扫，未发现转移者对侧颈区淋巴结不做处理 [38]。Shiyang Liu等的研究表明，BRAF V600E蛋白表达阴性更可能导致侧颈区淋巴结转移(lateral cervical lymph node metastasis, LLNM) [40]。Changjiao Yan等人的研究显示：在我国2048例PTC患者中，B-RAF突变阴性突变状态与LLNM高度相关 [41]。Chang Deng等人研究发现BRAF突变阴性的PTC患者的LLNM发生率明显高于BRAFV600E突变阳性的PTC患者 [42]。Xiangqian Zheng等人的研究也显示BRAF突变与LLNM无显著关联 [43]，因此B-RAF突变患者预防性侧颈区淋巴结清扫的必要性存在一定争议，需进一步深入探讨。

5.1.3. BRAF V600E与甲状腺全切术

张茂杰等人的研究表明，甲状腺BRAF V600E突变阳性的患者肿瘤双侧发病率与单侧发病率并无明显差异，P > 0.05 [44]。《2021年分化型甲状腺癌诊疗指南》未明确指出单侧甲状腺组织BRAF突变基因阳性的患者需行甲状腺全切术 [37]，单侧甲状腺组织BRAF突变基因阳性的患者是否选择甲状腺全切术仍存在争议，还需进一步深入研究。

5.2. BRAF V600E与放射性碘治疗

PTC细胞表达的钠-碘转运体(Sodium-Iodide symporter, NIS)具有捕获放射性碘的能力 [45]，因此甲状腺癌可以采用放射性碘(radioactive iodine, RAI)治疗，又称为“I131治疗”。该方法有效降低PTC术后复发风险甚至术后死亡率 [38] [46]。I131治疗有三个目的：一是利用具有放射性的I131只在甲状腺组织中聚集的特点铲除手术中未切除的甲状腺组织，以达到减小癌症复发几率的目的；二是对高度怀疑恶性但未确诊的甲状腺组织进行辅助治疗；三是对残留或者复发的甲状腺恶性组织进行治疗 [36] [45]。但I131治疗对部分BRAF基因突变的患者治疗效果有限。BRAF基因改变被认为与TC中NIS表达减少有关 [45] [47]，其激活MAP激酶信号通路可以降低NIS的表达，导致PTC细胞碘摄取能力下降并产生RAI治疗耐药性 [47]。

5.3. BRAF V600E与靶向治疗

对于BRAF V600E基因突变阳性的放射性碘难治性TC，靶向治疗显得尤为重要 [47]。其中PTC被归类为MAPK驱动的肿瘤，两大主要信号驱动因子是BRAF V600E突变和Ras突变，多激酶抑制剂药物(multiple kinase inhibitor drugs, MKIs)就是通过阻断MAPK通路发挥作用 [48]。BRAF突变阳性的PTC应用MKIs后，药物作用于相对应靶点可使部分患者肿瘤体积缩小、无进展生存期延长 [49]，但这些药物不能治愈，因此只能用于进展性或症状性疾病患者 [4] [50]。美国食品药品管理局(FDA)批准的MKIs有：用于晚期、复发和放射性碘难治性DTC的Sorafenib和Lenvatinib等；用于MTC的Vandetanib和Cabozantinib等 [48] [51]。这四款MKIs主要通过与ATP在酪氨酸激酶受体(TKR)上的结合位点竞争来发挥其抗肿瘤活性，部分通过阻断MAPK通路的几个中心介质来发挥其抗肿瘤活性 [51] [52] [53] [54]，这些药物可明显抑制肿瘤生长，延长生存时间 [49]。但不同研究团队所测得上述四种药物的无进展生存时间(Progress Free Survival, PFS)变化很大 [55] - [60]，几乎所有使用这些新药物治疗的患者都经历了不良反应(adverse effects, AEs) [61]，其临床疗效及对患者生活质量的影响有待进一步考察。另外，Vemurafenib选择性抑制突变BRAF激酶被FDA批准用于治疗BRAF突变型黑色素瘤，是一种治疗BRAF突变型PTC潜在药物，有望成为第一个用于治疗BRAF突变PTC的BRAF抑制剂 [22]。免疫检查点抑制剂、靶向肿瘤干细胞药物等新型药物也是未来研究的新领域。

5.4. BRAF V600E与免疫治疗

PTC肿瘤细胞已经发展出各种免疫逃逸机制来操纵宿主免疫系统和免疫微环境，以避免被免疫细胞识别和消除。所采用的策略包括上调免疫抑制分子、下调抗原展示或招募特定抑制细胞群 [62]。

5.4.1. BRAF抑制剂PLX4032和抗PD-1抗体联合治疗

相关研究表明：BRAFV600E突变通过转化生长因子Smad1/Smad3途径损害了tsMHCII的表达，从而增强了免疫逃逸。在该研究的临床前小鼠模型中，以PLX4032和抗PD-1抗体为靶点联合治疗可促进免疫系统识别和消除PTC，为晚期PTC患者提供了一种有效的治疗策略 [63]。

5.4.2. BRAF抑制剂PLX4720与抗PD-1/PDL1抗体联合治疗

另有研究表明：PLX4720与抗PD-L1/PD-1抗体联合应用可显著缩小肿瘤体积，延长生存期，提高抗肿瘤免疫功能 [62]。

5.4.3. IL-12免疫治疗

在Ranjit S Parhar等人的研究中，IL-12免疫治疗的小鼠存活率显著提高。促炎性异二聚体细胞因子具有很强的抗肿瘤活性，白细胞介素-12 (IL-12)是其中之一。NK细胞和CD8 + T细胞参与肿瘤细胞的杀伤，但转化生长因子-β (TGF-β)对NK细胞和CD8 + T细胞的抗肿瘤活性起遏制作用，IL-12可完全逆转免疫抑制，抗转化生长因子-β抗体也可部分恢复免疫抑制，因此IL-12免疫治疗对PTC有效，为后续应用于甲状腺癌辅助治疗提供了可能性 [64]。

6. BRAF V600E与预后评估

BRAF突变在超过50%的PTC病例中存在，并且突变与预后不良有关 [34] [35] [36]。相关研究已经报道了BRAF V600E突变与PTC肿瘤侵袭性之间的关联，包括更大的肿瘤大小，更高的甲状腺外侵和淋巴结转移率，更高的复发率，以及更高的癌症相关死亡率 [34] [65] [66] [67]。在Rossella Elisei等人的研究中，BRAF V600E基因在60岁以上(P = 0.02)、存在血管侵犯(P = 0.02)、晚期(P=0.03)的患者中更常见，突变组患者较难治愈、存活率低且死亡率更高，BRAF V600E突变是一个不依赖于其他临床病理特征的不良预后因素 [67]。一部分突变的PTC患者甚至可能转变为预后不佳的间变性癌 [68]。因此BRAF基因是否突变可以判断PTC预后风险 [27] [34] [37] [38]。美国《Thyroid》杂志刊登的《成人甲状腺结节与DTC诊治指南(2015版)》将BRAF基因突变与肿瘤体积大小、患者是否出现腺外局部侵犯等特征相结合归入术后复发风险评估体系 [38]。我国《甲状腺诊疗规范(2021年版)》将肿瘤组织类型、原发瘤体大小、患者是否出现腺体外局部侵犯、是否出现血管浸润、BRAFV600E基因是否突变、是否出现远处转移等作为判断影响预后的几个相关重要因素 [37]。

此外Xing Chen等人最新研究显示WT1具有促进携带BRAFV600E突变PTC细胞的进展和发育的功能，是一个有前景的预后生物标志物 [69]。

7. 展望

TC的基础理论研究、临床诊断标准以及治疗策略一直是医学领域的热点，随着BRAF V600E基因突变研究的深入，越来越多的诊断治疗策略被提出。BRAF V600E作为甲状腺癌隐藏的生物特征标志物，对甲状腺癌诊断、病情评估、治疗策略及预后判断起重要作用。目前BRAF V600E基因检测阳性是否需要预防性颈部淋巴结清扫、单侧BRAF基因阳性患者是否行预防性甲状腺全切术仍存在一定争议，后期需要进一步研究和探索。

文章引用

刘延泽,刘嘉琦,李 良. BRAF V600E在甲状腺乳头状癌临床应用性中的研究进展
Research Progress of BRAF V600E Gene Mutation in Papillary Thyroid Carcinoma[J]. 临床医学进展, 2022, 12(09): 8499-8507. https://doi.org/10.12677/ACM.2022.1291227

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    70. NOTES

    *第一作者。

    #通讯作者。

期刊菜单