任會(huì)強(qiáng) 董麗儒 宋旭東

華北理工大學(xué)附屬醫(yī)院病理科 河北唐山 063000

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EGFR基因突變與非小細(xì)胞肺癌相關(guān)研究進(jìn)展

任會(huì)強(qiáng) 董麗儒 宋旭東

華北理工大學(xué)附屬醫(yī)院病理科 河北唐山 063000

非小細(xì)胞肺癌 EGFR EGFR基因突變 EGFR-TKIs

目前，肺癌依然是導(dǎo)致人類腫瘤性致死的首位疾病，全球每年因肺癌死亡的人數(shù)超過(guò)100萬(wàn)，其中80%～90%的患者為非小細(xì)胞肺癌(non-small-cell lung cancer,NSCLC)[1]。NSCLC占原發(fā)性肺癌的80%～85%[2]。雖然對(duì)肺癌的檢測(cè)和治療手段在不斷的進(jìn)步，但大多數(shù)肺癌患者預(yù)后仍然很差，5年生存率僅為10%～15%[3]。近年來(lái)，隨著精準(zhǔn)醫(yī)學(xué)的提倡、發(fā)展，個(gè)體化治療成為NSCLC治療的新方向。這種治療基于腫瘤的分子特征，針對(duì)表皮生長(zhǎng)因子相關(guān)受體(epidermal growth factor receptor，EGFR)基因突變位點(diǎn)選擇最佳的治療方案，EGFR酪氨酸激酶抑制劑(EGFR tyrosine kinase inhibitors ,EGFR-TKIs)治療對(duì)有EGFR基因突變的患者較沒(méi)有EGFR基因突變的患者效果更好[4～7],使患者獲得最好的療效，延長(zhǎng)其生存時(shí)間、提高生活質(zhì)量。所以檢測(cè)EGFR基因是否突變成為預(yù)測(cè)EGFR-TKIs療效的指標(biāo)?，F(xiàn)對(duì)EGFR基因突變與NSCLC相關(guān)研究的進(jìn)展綜述如下。

1 EGFR的分子生物學(xué)結(jié)構(gòu)及功能

EGFR屬于酪氨酸激酶I型受體家族，其家族成員主要包括EGFR HER1、HER2、HER3、HER4四種同源受體。研究發(fā)現(xiàn)，EGFR廣泛分布于各種上皮細(xì)胞的細(xì)胞膜上，分為胞外區(qū)、跨膜區(qū)、胞內(nèi)區(qū)三個(gè)部分。目前報(bào)道EGFR配體有表皮生長(zhǎng)因子EGF、轉(zhuǎn)化生長(zhǎng)因子TGF、結(jié)合肝素的EGF、雙調(diào)蛋白、B-cellulin等[8]。EGFR主要信號(hào)轉(zhuǎn)導(dǎo)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號(hào)染色體短臂7p12-14區(qū)，共118kb，由28個(gè)外顯子組成。其酪氨酸激酶功能區(qū)由外顯子18-24編碼，其中外顯子18-20編碼N端半段結(jié)構(gòu)(N terminal half,N-Lobe),外顯子21-24編碼C端半段結(jié)構(gòu)(C terminal half,C-Lobe)。EGFR是癌癥生長(zhǎng)的刺激因素。EGFR基因突變可使EGFR在沒(méi)有配體與其結(jié)合的情況下激活下游分子，從而引起腫瘤等疾病的發(fā)生[10]。有研究顯示[11]EGFR基因突變和蛋白的過(guò)表達(dá)都可以激化下游信號(hào)通路，這與癌癥的的發(fā)生有密切的關(guān)系，特別是肺癌。

2 EGFR基因突變的特點(diǎn)

研究表明[12]EGFR基因突變主要包括18外顯子突變和19外顯子的缺失突變(主要是19外顯子的多個(gè)核苷酸框架缺失突變引起4個(gè)氨基酸的缺失) 、20外顯子的插入或T790M和21外顯子上的點(diǎn)突變引起858位點(diǎn)氨基酸替代突變。另一項(xiàng)研究顯示[13]EGFR基因的28個(gè)外顯子中，第18-21外顯子編碼酪氨酸激酶區(qū)；EGFR基因突變部位分散在整個(gè)酪氨酸激酶區(qū)，19外顯子的缺失突變和21外顯子的L858R突變是最常見的突變類型。相似的研究表明[16]EGFR基因的經(jīng)典突變是19外顯子的缺失突變和21外顯子的L858R突變，兩者分別占EGFR基因突變的45%和40%。另一項(xiàng)試驗(yàn)[17]表明19外顯子的突變率最高，占全部突變的60%以上。Fukui等[18]研究發(fā)現(xiàn)EGFR基因突變有以下類型:19外顯子的缺失突變、密碼子719處的點(diǎn)突變(G719X)、20外顯子的插入突變、21外顯子的點(diǎn)突變。19外顯子的缺失突變包括從亮氨酸-747到谷氨酸-749，定位于酪氨酸激酶C螺旋區(qū)N端，此處缺失發(fā)生率為44%。20外顯子出現(xiàn)的突變發(fā)生率為5%，G719X發(fā)生率為4%。在外顯子21處的點(diǎn)突變是最常見的EGFR酪氨酸激酶區(qū)點(diǎn)突變，發(fā)生率為41%。Lynch等[14,19]均報(bào)道發(fā)現(xiàn)在EGFR基因TK區(qū)域外顯子18-23存在基因突變。該突變導(dǎo)致EGFR基因上ATP結(jié)合位點(diǎn)的缺口，該位點(diǎn)正是酪氨酸激酶抑制劑(TKIs)的結(jié)合位點(diǎn)。據(jù)研究表明[20]20%的NSCLC患者有EGFR基因突變，主要位于酪氨酸激酶區(qū)域的19外顯子堿基對(duì)缺失(delE746_A750，占54%)或21外顯子的點(diǎn)突變(L858R，占43%)。鄭軍等[21]研究214例NSCLC EGFR基因總突變率為45.8%(97/214)。其中18外顯子突變發(fā)生率為0.93%(2/214)、19外顯子突變發(fā)生率為22.0%(47/214)，均為缺失突變；20外顯子突變發(fā)生率為2.3%(5/214)，其中有4例缺失突變，1例T790M突變；21外顯子突變率為20.6%(44/214)，均為L(zhǎng)858R突變。研究中出現(xiàn)2例19外顯子的缺失突變和21外顯子的L858R突變的雙重突變，此現(xiàn)象提示肺癌患者中可存在EGFR基因聯(lián)合突變。

EGFR基因突變并非都有良好的分子靶向治療效果，T790M突變則提示NSCLC對(duì)TKI耐藥。T790M位于20外顯子ATP結(jié)合口袋，被命名為“看門人殘留”，其突變是在激酶域的790位點(diǎn)蛋氨酸替代蘇氨酸，導(dǎo)致位阻效應(yīng)，減弱EGFR與ATP的結(jié)合力；ATP結(jié)合口袋對(duì)ATP的結(jié)合能力因T790M基因突變而增強(qiáng)，從而與TKIs競(jìng)爭(zhēng)性的結(jié)合ATP；T790M突變也可使L858R突變的EGFR基因與ATP親和力增強(qiáng)，這三個(gè)原因就是耐藥發(fā)生的機(jī)制[11,22]。沒(méi)有使用TKIs治療的患者，也會(huì)出現(xiàn)T790M突變，突變率為2.7%～40%[23]。所有NSCLC(有19外顯子缺失突變和21外顯子點(diǎn)突變)患者在接受EGFR-TKIs治療后，都會(huì)發(fā)生獲得性耐受，其中50%患者20外顯子(T790M)會(huì)有T790M基因二次突變，這種突變?cè)谥委熢缙诤苌侔l(fā)生[24,25]。T790M基因突變還可與其他突變同時(shí)存在，如L858R 和 D761Y。與L858R突變同時(shí)存在時(shí)，T790M基因可增強(qiáng)磷酸化活性。突變共存可導(dǎo)致肺癌細(xì)胞存活，這表明T790M基因是一個(gè)致癌基因[26,27]。此外還存在非T790M的二次突變，主要有D761Y、L747S和T854A[28～30]。這些突變導(dǎo)致EGFR基因突變對(duì)EGFR-TKIs的敏感性下降，其耐藥的機(jī)制還不清楚[11]。另外，最近的研究[30,31]顯示，在EGFR基因20外顯子上發(fā)現(xiàn)了一種新插入突變(Pro772-His773insGlnCysPro)，這種突變發(fā)生于不吸煙的患者[32,33]。但這些非T790M的突變發(fā)生率很低。

3 EGFR基因突變與NSCLC臨床病理學(xué)特征

有研究[34,35]顯示，大約有10%～30%的NSCLC患者發(fā)生EGFR基因突變。張靜等[36]在檢測(cè)170例NSCLC研究中發(fā)現(xiàn)腺癌、鱗癌和大細(xì)胞癌EGFR基因突變的檢出率分別為:60.3%(82/136)、0%(0/24)和20%(2/10)。此研究顯示肺腺癌患者中EGFR基因突變率明顯高于鱗癌及大細(xì)胞癌患者，肺腺癌與非腺癌EGFR基因突變比較差異有統(tǒng)計(jì)學(xué)意義，136例腺癌中細(xì)支氣管肺泡癌(15/22)和其他類型腺癌(67/114)的EGFR基因突變率差異無(wú)統(tǒng)計(jì)學(xué)意義。鄭軍等[21]的研究顯示，在肺腺癌組織中的EGFR基因突變率為50.3%(93/185)，明顯高于肺鱗狀細(xì)胞癌17.2%(5/29)。Hisayuki等[20]研究顯示，肺腺癌EGFR基因突變率為40%。另一項(xiàng)研究發(fā)現(xiàn)[38]肺腺癌和肺腺鱗癌的突變發(fā)生率高于其他病理類型。

韓寶惠等[37]發(fā)現(xiàn)EGFR基因突變主要見于女性、腺癌及腺鱗癌等患者。Paez等研究發(fā)現(xiàn)[19]EGFR基因突變與性別、種族、吸煙、病理類型有關(guān)，亞洲人群、女性、非吸煙、肺腺癌的NSCLC患者突變率較高,女性和非吸煙的NSCLC患者EGFR基因突變率高于男性和吸煙患者。后續(xù)的多項(xiàng)臨床研究[38,39]再次證實(shí)女性、不吸煙的NSCLC患者EGFR突變率明顯高于男性和吸煙的NSCLC患者。另一項(xiàng)研究發(fā)現(xiàn)[40]女性NSCLC患者的EGFR突變率高于男性，并且非吸煙NSCLC患者EGFR突變率高于吸煙者。國(guó)外一項(xiàng)研究[20]顯示，女性NSCLC患者EGFR基因突變率為42%，亞洲種族NSCLC患者EGFR基因突變率為30%,非吸煙NSCLC患者EGFR基因突變率為51%。國(guó)內(nèi)一項(xiàng)研究[21]顯示，女性患者EGFR突變率為57.0%(57/100),高于男性[36.0%(41/114)]。張靜等[36]對(duì)170例NSCLC患者的EGFR基因突變情況的研究表明，EGFR基因突變常見于女性、不吸煙、腫瘤大小≤3cm且分化程度較好的NSCLC患者。Dearden等[41]研究顯示，亞洲地區(qū)NSCLC患者EGFR基因突變率為47.9%。該數(shù)據(jù)與Midha等[42]對(duì)亞洲地區(qū)NSCLC患者EGFR基因突變情況研究所得的數(shù)據(jù)(47%)相近。并且，亞洲地區(qū)的NSCLC女性患者的EGFR基因突變率高于男性患者(60%:37%)，該地區(qū)非吸煙NSCLC患者EGFR基因突變率高于吸煙患者(64%:33%)。因此，EGFR基因突變通常發(fā)生在NSCLC患者的以下亞群：非吸煙、女性、東亞人群、支氣管肺泡腺癌和中分化的腫瘤患者[33,43,44]。研究顯示[41]盡管EGFR基因突變高發(fā)于女性、非吸煙和亞洲人群等NSCLC患者，但是也可以發(fā)生在這三類人群之外的患者中。Yuankai等[45]的研究發(fā)現(xiàn)超過(guò)50%的NSCLC患者的EGFR基因突變不是女性非吸煙患者。

劉紅雨等[40]研究發(fā)現(xiàn), EGFR基因19外顯子和21外顯子的突變與肺癌患者的年齡、臨床分期、腫瘤大小、轉(zhuǎn)移情況等沒(méi)有明顯的關(guān)系。有研究[37]顯示EGFR基因突變與患者的年齡、淋巴結(jié)是否轉(zhuǎn)移及疾病pTNM分期等無(wú)相關(guān)性。相似的研究[21]顯示EGFR基因突變率在患者年齡分組中無(wú)顯著性差異。但多數(shù)研究報(bào)道[46～48]顯示EGFR基因突變?cè)谟辛馨徒Y(jié)轉(zhuǎn)移的NSCLC患者中的發(fā)生率高于無(wú)淋巴結(jié)轉(zhuǎn)移的患者，而與腫瘤臨床分期及病理分級(jí)無(wú)顯著性相關(guān)。

4 EGFR基因突變與NSCLC臨床治療

有一些EGFR基因突變會(huì)增強(qiáng)EGFR-TKIs的敏感性，比如L858R和19外顯子的缺失。21外顯子L858R位點(diǎn)突變可減低ATP結(jié)合的親和力，這種ATP親和力的降低實(shí)質(zhì)上建立了一個(gè)“治療窗口”，這種致癌性的EGFR基因突變可更容易的被TKIs抑制，從而替代親和力低的ATP[22]。這就為EGFR-TKIs治療有19和21位點(diǎn)突變的NSCLC的患者提供了方案。第一代EGFR-TKIs(吉非替尼和埃羅替尼)可逆的競(jìng)爭(zhēng)ATP結(jié)合位點(diǎn)，從而阻止EGFR導(dǎo)致的下游信號(hào)激活[49]。TKIs也可導(dǎo)致腫瘤細(xì)胞的死亡[11]。有研究[50,51]顯示，與應(yīng)用卡鉑/紫杉醇治療的患者的中位無(wú)進(jìn)展生存期(progression free survival，PFS)相比，吉非替尼可顯著延長(zhǎng)有EGFR基因突變NSCLC患者的中位PFS(平均為9.5:6.3個(gè)月)。據(jù)一些研究顯示[52,53]，吉非替尼與卡鉑/紫杉醇作為一線藥物治療有EGFR基因突變的亞洲患者，中位PFS 9.2:6.3個(gè)月(P<0.0001)；埃羅替尼與卡鉑/紫杉醇化療作為一線藥物治療EGFR基因突變的亞洲患者進(jìn)行療效比較，中位PFS 13.1:4.6個(gè)月?？ㄣK/紫杉醇較EGFR-TKIs對(duì)有EGFR基因擴(kuò)增的NSCLC患者的療效好，并且對(duì)于沒(méi)有EGFR基因突變的患者，卡鉑/紫杉醇較EGFR-TKIs療效顯著(中位 PFS 5.5:1.5個(gè)月，P<0.001)[19]。在有EGFR基因突變的NSCLC患者(n=261)，吉非替尼比化療的PFS長(zhǎng)，相對(duì)危險(xiǎn)比更高(71.2%：47.3%)；相反，在無(wú)EGFR基因突變的群組患者，PFS顯著縮短，相對(duì)危險(xiǎn)比更低(1.1%:23.5%)[23]。因此再次證實(shí)，EGFR基因突變位點(diǎn)決定EGFR-TKIs的臨床應(yīng)用療效。然而，所有的患者初次應(yīng)用吉非替尼和埃羅替尼效果非常顯著，6到12個(gè)月之后會(huì)產(chǎn)生獲得性耐藥[24,25]。一些耐藥機(jī)制研究已經(jīng)發(fā)現(xiàn)[54]大約50%的獲得性耐藥是由于EGFR基因20外顯子T790M的二次突變導(dǎo)致的，T790M突變會(huì)減低EGFR-TKIs與ATP結(jié)合的敏感度，但是還有30%的獲得性耐受病例仍然無(wú)法解釋[29]，這需要進(jìn)一步的研究。

Oxnard等[55]發(fā)現(xiàn)TKIs治療后活檢有T790M突變的患者比沒(méi)有突變的患者的預(yù)后生存時(shí)間更長(zhǎng)(19:12個(gè)月)。Kuiper等[56]對(duì)66例有EGFR基因突變的NSCLC患者研究顯示，用EGFR-TKIs治療post-TKIs活檢有T790M突變的患者比沒(méi)有突變患者有更長(zhǎng)的PFS(14.2:11.1)個(gè)月，并且有更長(zhǎng)的總生存期(45.9:29.8)個(gè)月。腫瘤有高的EGFR基因拷貝數(shù)，并有EGFR基因突變的患者，吉非替尼能顯著延長(zhǎng)其PFS；腫瘤有高的EGFR基因拷貝數(shù)，沒(méi)有EGFR基因突變的患者，應(yīng)用吉非替尼比應(yīng)用卡鉑/紫杉醇的PFS還要短[23]，這再一次表明EGFR基因突變是應(yīng)用EGFR-TKIs治療的指針。另有研究[57]顯示，應(yīng)用EGFR-TKIs治療出現(xiàn)T790M突變的患者較沒(méi)有出現(xiàn)此突變的患者有更長(zhǎng)的PFS。

西妥昔單抗是一單克隆抗體，通過(guò)結(jié)合胞外區(qū)域來(lái)抑制EGFR基因，從而封鎖配體依賴性受體的激活[58];也可通過(guò)調(diào)節(jié)受體的內(nèi)吞和退化來(lái)抑制EGFR信號(hào)，因此也可減弱配體依賴的EGFR信號(hào)[32]。研究顯示[59]西妥昔單抗與雙鉑化療聯(lián)用治療NSCLC相比,患者的總生存時(shí)間為(11.3:10.1)個(gè)月，用西妥昔單抗治療的患者有更長(zhǎng)的總生存時(shí)間。

Federico等[60]研究15例19外顯子缺失突變和7例21外顯子點(diǎn)突變的患者在接受化療時(shí)發(fā)現(xiàn)，19外顯子缺失突變的預(yù)后更好。Jackman等[61]研究36例接受EGFR-TKIs治療的19和21外顯子突變的NSCLC患者預(yù)后顯示，19(delp.729-761)比L858R突變的患者的時(shí)間進(jìn)程有顯著提高(24:10個(gè)月)，有19外顯子突變的患者比21外顯子突變的患者有更高的危險(xiǎn)比(73%:50%)。這種現(xiàn)象還沒(méi)有一個(gè)科學(xué)的解釋，可能與19外顯子對(duì)EGFR-TKI的敏感性更高有關(guān)[62]。這些研究表明，不同的EGFR基因突變的患者腫瘤有著不同的生物學(xué)特性。

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(2016-05-05 收稿)(張愛國(guó) 編輯)

2016年河北省政府資助臨床醫(yī)學(xué)優(yōu)秀人才培養(yǎng)和基礎(chǔ)課題研究項(xiàng)目(編號(hào)：361036)。

任會(huì)強(qiáng)(1988-)，男，碩士研究生。研究方向：肺腫瘤。

宋旭東。

R 73

A

2095-2694(2016)05-413-08