EGFR基因突变与非小细胞肺癌相关研究进展

任会强 董丽儒 宋旭东

华北理工大学附属医院病理科 河北唐山 063000



EGFR基因突变与非小细胞肺癌相关研究进展

任会强 董丽儒 宋旭东

华北理工大学附属医院病理科 河北唐山 063000

非小细胞肺癌 EGFR EGFR基因突变 EGFR-TKIs

目前，肺癌依然是导致人类肿瘤性致死的首位疾病，全球每年因肺癌死亡的人数超过100万，其中80%～90%的患者为非小细胞肺癌(non-small-cell lung cancer,NSCLC)[1]。NSCLC占原发性肺癌的80%～85%[2]。虽然对肺癌的检测和治疗手段在不断的进步，但大多数肺癌患者预后仍然很差，5年生存率仅为10%～15%[3]。近年来，随着精准医学的提倡、发展，个体化治疗成为NSCLC治疗的新方向。这种治疗基于肿瘤的分子特征，针对表皮生长因子相关受体(epidermal growth factor receptor，EGFR)基因突变位点选择最佳的治疗方案，EGFR酪氨酸激酶抑制剂(EGFR tyrosine kinase inhibitors ,EGFR-TKIs)治疗对有EGFR基因突变的患者较没有EGFR基因突变的患者效果更好[4～7],使患者获得最好的疗效，延长其生存时间、提高生活质量。所以检测EGFR基因是否突变成为预测EGFR-TKIs疗效的指标。现对EGFR基因突变与NSCLC相关研究的进展综述如下。

1 EGFR的分子生物学结构及功能

EGFR属于酪氨酸激酶I型受体家族，其家族成员主要包括EGFR HER1、HER2、HER3、HER4四种同源受体。研究发现，EGFR广泛分布于各种上皮细胞的细胞膜上，分为胞外区、跨膜区、胞内区三个部分。目前报道EGFR配体有表皮生长因子EGF、转化生长因子TGF、结合肝素的EGF、双调蛋白、B-cellulin等[8]。EGFR主要信号转导途有RAS-RAF-MEK-ERK-MAPK通路、PLC-γ通路、PI3K-PDK通路和JAK-STAT通路[9]。

EGFR的基因位于7号染色体短臂7p12-14区，共118kb，由28个外显子组成。其酪氨酸激酶功能区由外显子18-24编码，其中外显子18-20编码N端半段结构(N terminal half,N-Lobe),外显子21-24编码C端半段结构(C terminal half,C-Lobe)。EGFR是癌症生长的刺激因素。EGFR基因突变可使EGFR在没有配体与其结合的情况下激活下游分子，从而引起肿瘤等疾病的发生[10]。有研究显示[11]EGFR基因突变和蛋白的过表达都可以激化下游信号通路，这与癌症的的发生有密切的关系，特别是肺癌。

2 EGFR基因突变的特点

研究表明[12]EGFR基因突变主要包括18外显子突变和19外显子的缺失突变(主要是19外显子的多个核苷酸框架缺失突变引起4个氨基酸的缺失) 、20外显子的插入或T790M和21外显子上的点突变引起858位点氨基酸替代突变。另一项研究显示[13]EGFR基因的28个外显子中，第18-21外显子编码酪氨酸激酶区；EGFR基因突变部位分散在整个酪氨酸激酶区，19外显子的缺失突变和21外显子的L858R突变是最常见的突变类型。相似的研究表明[16]EGFR基因的经典突变是19外显子的缺失突变和21外显子的L858R突变，两者分别占EGFR基因突变的45%和40%。另一项试验[17]表明19外显子的突变率最高，占全部突变的60%以上。Fukui等[18]研究发现EGFR基因突变有以下类型:19外显子的缺失突变、密码子719处的点突变(G719X)、20外显子的插入突变、21外显子的点突变。19外显子的缺失突变包括从亮氨酸-747到谷氨酸-749，定位于酪氨酸激酶C螺旋区N端，此处缺失发生率为44%。20外显子出现的突变发生率为5%，G719X发生率为4%。在外显子21处的点突变是最常见的EGFR酪氨酸激酶区点突变，发生率为41%。Lynch等[14,19]均报道发现在EGFR基因TK区域外显子18-23存在基因突变。该突变导致EGFR基因上ATP结合位点的缺口，该位点正是酪氨酸激酶抑制剂(TKIs)的结合位点。据研究表明[20]20%的NSCLC患者有EGFR基因突变，主要位于酪氨酸激酶区域的19外显子碱基对缺失(delE746_A750，占54%)或21外显子的点突变(L858R，占43%)。郑军等[21]研究214例NSCLC EGFR基因总突变率为45.8%(97/214)。其中18外显子突变发生率为0.93%(2/214)、19外显子突变发生率为22.0%(47/214)，均为缺失突变；20外显子突变发生率为2.3%(5/214)，其中有4例缺失突变，1例T790M突变；21外显子突变率为20.6%(44/214)，均为L858R突变。研究中出现2例19外显子的缺失突变和21外显子的L858R突变的双重突变，此现象提示肺癌患者中可存在EGFR基因联合突变。

EGFR基因突变并非都有良好的分子靶向治疗效果，T790M突变则提示NSCLC对TKI耐药。T790M位于20外显子ATP结合口袋，被命名为“看门人残留”，其突变是在激酶域的790位点蛋氨酸替代苏氨酸，导致位阻效应，减弱EGFR与ATP的结合力；ATP结合口袋对ATP的结合能力因T790M基因突变而增强，从而与TKIs竞争性的结合ATP；T790M突变也可使L858R突变的EGFR基因与ATP亲和力增强，这三个原因就是耐药发生的机制[11,22]。没有使用TKIs治疗的患者，也会出现T790M突变，突变率为2.7%～40%[23]。所有NSCLC(有19外显子缺失突变和21外显子点突变)患者在接受EGFR-TKIs治疗后，都会发生获得性耐受，其中50%患者20外显子(T790M)会有T790M基因二次突变，这种突变在治疗早期很少发生[24,25]。T790M基因突变还可与其他突变同时存在，如L858R 和 D761Y。与L858R突变同时存在时，T790M基因可增强磷酸化活性。突变共存可导致肺癌细胞存活，这表明T790M基因是一个致癌基因[26,27]。此外还存在非T790M的二次突变，主要有D761Y、L747S和T854A[28～30]。这些突变导致EGFR基因突变对EGFR-TKIs的敏感性下降，其耐药的机制还不清楚[11]。另外，最近的研究[30,31]显示，在EGFR基因20外显子上发现了一种新插入突变(Pro772-His773insGlnCysPro)，这种突变发生于不吸烟的患者[32,33]。但这些非T790M的突变发生率很低。

3 EGFR基因突变与NSCLC临床病理学特征

有研究[34,35]显示，大约有10%～30%的NSCLC患者发生EGFR基因突变。张静等[36]在检测170例NSCLC研究中发现腺癌、鳞癌和大细胞癌EGFR基因突变的检出率分别为:60.3%(82/136)、0%(0/24)和20%(2/10)。此研究显示肺腺癌患者中EGFR基因突变率明显高于鳞癌及大细胞癌患者，肺腺癌与非腺癌EGFR基因突变比较差异有统计学意义，136例腺癌中细支气管肺泡癌(15/22)和其他类型腺癌(67/114)的EGFR基因突变率差异无统计学意义。郑军等[21]的研究显示，在肺腺癌组织中的EGFR基因突变率为50.3%(93/185)，明显高于肺鳞状细胞癌17.2%(5/29)。Hisayuki等[20]研究显示，肺腺癌EGFR基因突变率为40%。另一项研究发现[38]肺腺癌和肺腺鳞癌的突变发生率高于其他病理类型。

韩宝惠等[37]发现EGFR基因突变主要见于女性、腺癌及腺鳞癌等患者。Paez等研究发现[19]EGFR基因突变与性别、种族、吸烟、病理类型有关，亚洲人群、女性、非吸烟、肺腺癌的NSCLC患者突变率较高,女性和非吸烟的NSCLC患者EGFR基因突变率高于男性和吸烟患者。后续的多项临床研究[38,39]再次证实女性、不吸烟的NSCLC患者EGFR突变率明显高于男性和吸烟的NSCLC患者。另一项研究发现[40]女性NSCLC患者的EGFR突变率高于男性，并且非吸烟NSCLC患者EGFR突变率高于吸烟者。国外一项研究[20]显示，女性NSCLC患者EGFR基因突变率为42%，亚洲种族NSCLC患者EGFR基因突变率为30%,非吸烟NSCLC患者EGFR基因突变率为51%。国内一项研究[21]显示，女性患者EGFR突变率为57.0%(57/100),高于男性[36.0%(41/114)]。张静等[36]对170例NSCLC患者的EGFR基因突变情况的研究表明，EGFR基因突变常见于女性、不吸烟、肿瘤大小≤3cm且分化程度较好的NSCLC患者。Dearden等[41]研究显示，亚洲地区NSCLC患者EGFR基因突变率为47.9%。该数据与Midha等[42]对亚洲地区NSCLC患者EGFR基因突变情况研究所得的数据(47%)相近。并且，亚洲地区的NSCLC女性患者的EGFR基因突变率高于男性患者(60%:37%)，该地区非吸烟NSCLC患者EGFR基因突变率高于吸烟患者(64%:33%)。因此，EGFR基因突变通常发生在NSCLC患者的以下亚群：非吸烟、女性、东亚人群、支气管肺泡腺癌和中分化的肿瘤患者[33,43,44]。研究显示[41]尽管EGFR基因突变高发于女性、非吸烟和亚洲人群等NSCLC患者，但是也可以发生在这三类人群之外的患者中。Yuankai等[45]的研究发现超过50%的NSCLC患者的EGFR基因突变不是女性非吸烟患者。

刘红雨等[40]研究发现, EGFR基因19外显子和21外显子的突变与肺癌患者的年龄、临床分期、肿瘤大小、转移情况等没有明显的关系。有研究[37]显示EGFR基因突变与患者的年龄、淋巴结是否转移及疾病pTNM分期等无相关性。相似的研究[21]显示EGFR基因突变率在患者年龄分组中无显著性差异。但多数研究报道[46～48]显示EGFR基因突变在有淋巴结转移的NSCLC患者中的发生率高于无淋巴结转移的患者，而与肿瘤临床分期及病理分级无显著性相关。

4 EGFR基因突变与NSCLC临床治疗

有一些EGFR基因突变会增强EGFR-TKIs的敏感性，比如L858R和19外显子的缺失。21外显子L858R位点突变可减低ATP结合的亲和力，这种ATP亲和力的降低实质上建立了一个“治疗窗口”，这种致癌性的EGFR基因突变可更容易的被TKIs抑制，从而替代亲和力低的ATP[22]。这就为EGFR-TKIs治疗有19和21位点突变的NSCLC的患者提供了方案。第一代EGFR-TKIs(吉非替尼和埃罗替尼)可逆的竞争ATP结合位点，从而阻止EGFR导致的下游信号激活[49]。TKIs也可导致肿瘤细胞的死亡[11]。有研究[50,51]显示，与应用卡铂/紫杉醇治疗的患者的中位无进展生存期(progression free survival，PFS)相比，吉非替尼可显著延长有EGFR基因突变NSCLC患者的中位PFS(平均为9.5:6.3个月)。据一些研究显示[52,53]，吉非替尼与卡铂/紫杉醇作为一线药物治疗有EGFR基因突变的亚洲患者，中位PFS 9.2:6.3个月(P<0.0001)；埃罗替尼与卡铂/紫杉醇化疗作为一线药物治疗EGFR基因突变的亚洲患者进行疗效比较，中位PFS 13.1:4.6个月。卡铂/紫杉醇较EGFR-TKIs对有EGFR基因扩增的NSCLC患者的疗效好，并且对于没有EGFR基因突变的患者，卡铂/紫杉醇较EGFR-TKIs疗效显著(中位 PFS 5.5:1.5个月，P<0.001)[19]。在有EGFR基因突变的NSCLC患者(n=261)，吉非替尼比化疗的PFS长，相对危险比更高(71.2%：47.3%)；相反，在无EGFR基因突变的群组患者，PFS显著缩短，相对危险比更低(1.1%:23.5%)[23]。因此再次证实，EGFR基因突变位点决定EGFR-TKIs的临床应用疗效。然而，所有的患者初次应用吉非替尼和埃罗替尼效果非常显著，6到12个月之后会产生获得性耐药[24,25]。一些耐药机制研究已经发现[54]大约50%的获得性耐药是由于EGFR基因20外显子T790M的二次突变导致的，T790M突变会减低EGFR-TKIs与ATP结合的敏感度，但是还有30%的获得性耐受病例仍然无法解释[29]，这需要进一步的研究。

Oxnard等[55]发现TKIs治疗后活检有T790M突变的患者比没有突变的患者的预后生存时间更长(19:12个月)。Kuiper等[56]对66例有EGFR基因突变的NSCLC患者研究显示，用EGFR-TKIs治疗post-TKIs活检有T790M突变的患者比没有突变患者有更长的PFS(14.2:11.1)个月，并且有更长的总生存期(45.9:29.8)个月。肿瘤有高的EGFR基因拷贝数，并有EGFR基因突变的患者，吉非替尼能显著延长其PFS；肿瘤有高的EGFR基因拷贝数，没有EGFR基因突变的患者，应用吉非替尼比应用卡铂/紫杉醇的PFS还要短[23]，这再一次表明EGFR基因突变是应用EGFR-TKIs治疗的指针。另有研究[57]显示，应用EGFR-TKIs治疗出现T790M突变的患者较没有出现此突变的患者有更长的PFS。

西妥昔单抗是一单克隆抗体，通过结合胞外区域来抑制EGFR基因，从而封锁配体依赖性受体的激活[58];也可通过调节受体的内吞和退化来抑制EGFR信号，因此也可减弱配体依赖的EGFR信号[32]。研究显示[59]西妥昔单抗与双铂化疗联用治疗NSCLC相比,患者的总生存时间为(11.3:10.1)个月，用西妥昔单抗治疗的患者有更长的总生存时间。

Federico等[60]研究15例19外显子缺失突变和7例21外显子点突变的患者在接受化疗时发现，19外显子缺失突变的预后更好。Jackman等[61]研究36例接受EGFR-TKIs治疗的19和21外显子突变的NSCLC患者预后显示，19(delp.729-761)比L858R突变的患者的时间进程有显著提高(24:10个月)，有19外显子突变的患者比21外显子突变的患者有更高的危险比(73%:50%)。这种现象还没有一个科学的解释，可能与19外显子对EGFR-TKI的敏感性更高有关[62]。这些研究表明，不同的EGFR基因突变的患者肿瘤有着不同的生物学特性。

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(2016-05-05 收稿)(张爱国 编辑)

2016年河北省政府资助临床医学优秀人才培养和基础课题研究项目(编号：361036)。

任会强(1988-)，男，硕士研究生。研究方向：肺肿瘤。

宋旭东。

R 73

A

2095-2694(2016)05-413-08