,

(Department of Radiology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin Clinical Research Center for Cancer, Tianjin 300060, China)

非小細(xì)胞肺癌(non-small cell lung cancer, NSCLC)約占所有肺癌的85%，其驅(qū)動(dòng)基因包括表皮生長(zhǎng)因子受體(epidermal growth factor receptor, EGFR)、KRAS、BRAF、PIK3CA及ALK基因等[1]。近年來(lái)，針對(duì)特異性基因或蛋白的靶向治療使晚期NSCLC患者得到良好的生存獲益，并提高了生活質(zhì)量，已成為最受關(guān)注和最有前途的治療手段之一。

獲得準(zhǔn)確的分子表型是指導(dǎo)NSCLC靶向治療的前提，然而，由于NSCLC的不均質(zhì)性，活檢獲得的小塊組織難以準(zhǔn)確反映腫瘤的基因突變情況，而反復(fù)多次的活檢在臨床并不可行；高昂的基因檢測(cè)費(fèi)用也在一定程度上限制了其臨床應(yīng)用。影像學(xué)檢查是NSCLC的常規(guī)檢查手段，可監(jiān)測(cè)腫瘤治療療效；影像學(xué)表現(xiàn)可全面反映腫瘤的病理生理學(xué)及分子生物學(xué)特征。影像組學(xué)技術(shù)從醫(yī)學(xué)影像(CT、MRI、PET等)中高通量地提取定量特征，將數(shù)字影像轉(zhuǎn)化為大量可挖掘的數(shù)據(jù)，從而成為臨床決策支持工具[2]。影像基因組學(xué)是研究影像組學(xué)數(shù)據(jù)與基因組學(xué)聯(lián)系的科學(xué)[3]，致力于揭示腫瘤的影像學(xué)特征(影像表型)與分子標(biāo)志物(分子表型)之間的關(guān)系，將臨床成像推進(jìn)到分子和基因組成像的時(shí)代[4]。靶向治療的發(fā)展促使研究者們積極探尋與NSCLC驅(qū)動(dòng)基因突變相關(guān)的影像標(biāo)志物。本文對(duì)NSCLC的CT特征與驅(qū)動(dòng)基因突變相關(guān)性的影像基因組學(xué)研究進(jìn)展進(jìn)行綜述。

1 NSCLC的CT特征與驅(qū)動(dòng)基因突變的相關(guān)性

1.1 EGFR基因突變與CT特征 EGFR突變最常發(fā)生于酪氨酸激酶功能區(qū)的18～21外顯子，其中19外顯子缺失和21外顯子L858R突變是最常見的EGFR藥物敏感突變，20外顯子的T790M突變與腫瘤耐藥有關(guān)[5]。EGFR突變多見于腺癌，亞洲人群突變率約為20%～60%，白種人突變率約5%～20%，多見于不吸煙的年輕女性[6]。針對(duì)EGFR靶點(diǎn)的酪氨酸激酶抑制劑的發(fā)展開創(chuàng)了肺癌個(gè)體化治療的新時(shí)代，針對(duì)此基因的靶向治療藥物包括第1代的吉非替尼、厄洛替尼及?？颂婺幔?代的阿法替尼和第3代的奧希替尼等。

研究[7-9]報(bào)道EGFR突變相關(guān)的CT特征包括小病灶、支氣管充氣征、胸膜凹陷征、空泡征、均勻強(qiáng)化、磨玻璃密度影(ground-glass opacity， GGO)、無(wú)肺氣腫或肺纖維化等，但各中心的研究結(jié)果并不完全一致。Gevaert等[9]發(fā)現(xiàn)腫瘤邊緣明顯不規(guī)則(毛刺、分葉或邊界不清)與EGFR突變相關(guān)，而其他研究者則未發(fā)現(xiàn)二者間具有相關(guān)性[7,10-11]。一項(xiàng)Meta分析[12]結(jié)果顯示亞實(shí)性病灶傾向于存在EGFR突變，而其他CT特征包括腫瘤大小、空洞、支氣管充氣征、分葉和毛刺等均與EGFR突變無(wú)相關(guān)。一些研究者[11,13-15]深入分析了與EGFR突變亞型相關(guān)的影像學(xué)特征。Lee等[13]對(duì)手術(shù)切除肺腺癌組織的研究顯示，21外顯子突變肺腺癌的GGO體積比例(61.7%±31.9%)明顯高于野生型(30.0%±38.5%；P=0.000 1)和19外顯子缺失者(28.9%±37.7%；P=0.000 6)。Hsu等[11]研究進(jìn)展期肺腺癌發(fā)現(xiàn)，21外顯子突變的腫瘤最大徑為(4.2±2.1)cm，大于19外顯子缺失者[(3.2±1.7)cm；P=0.02)]，且19外顯子缺失的肺腺癌患者較野生型(P=0.004)或21外顯子突變者(P=0.01)更常出現(xiàn)支氣管充氣征。Zhao等[14]亦發(fā)現(xiàn)支氣管充氣征是19外顯子缺失的獨(dú)立預(yù)測(cè)因子(P=0.007，優(yōu)勢(shì)比2.91)。Shi等[15]發(fā)現(xiàn)19外顯子缺失相關(guān)的影像特征包括腫瘤較小、女性、胸膜凹陷征及無(wú)肺纖維化，而21外顯子突變相關(guān)的特征包括毛刺、亞實(shí)性病灶和無(wú)吸煙史。

除傳統(tǒng)影像特征外，近年來(lái)影像組學(xué)也用于探尋NSCLC計(jì)算機(jī)定量特征與EGFR突變的相關(guān)性。Sacconi等[16]發(fā)現(xiàn)CT值均數(shù)、標(biāo)準(zhǔn)差和偏度與晚期肺腺癌的EGFR突變相關(guān)。Liu等[17]提取了298例手術(shù)切除肺腺癌組織的219個(gè)3D特征，發(fā)現(xiàn)其中11個(gè)與EGFR突變相關(guān)，多元邏輯回歸模型顯示增加影像組學(xué)特征后，可顯著提高臨床特征對(duì)肺腺癌的EGFR突變預(yù)測(cè)能力[曲線下面積(area under the curve, AUC)=0.667 vs AUC=0.709；P<0.000 1]。Aerts等[18]觀察47例早期NSCLC吉非替尼治療前后的影像組學(xué)特征，以預(yù)測(cè)EGFR突變，發(fā)現(xiàn)治療前Laws Energy-10 (AUC=0.67，P=0.03)可預(yù)測(cè)EGFR突變；治療前后特征變化中，除腫瘤體積和最大徑變化外，Gabor Energy (dir135-w3)的變化亦可預(yù)測(cè)EGFR突變(AUC=0.74，P=0.000 3)。Rios Velazquez等[19]觀察來(lái)自4個(gè)醫(yī)療中心的763例肺腺癌患者的影像組學(xué)特征，分析其與EGFR和KRAS突變的關(guān)系，單因素分析顯示16個(gè)特征與EGFR突變相關(guān)，這些特征均提示EGFR突變的腫瘤更不均質(zhì)；影像組學(xué)特征可區(qū)分EGFR陽(yáng)性與EGFR陰性(AUC=0.69)，結(jié)合臨床特征可顯著提高預(yù)測(cè)的準(zhǔn)確率(AUC=0.75)，且可區(qū)分EGFR陽(yáng)性及KRAS陽(yáng)性(AUC=0.80)，結(jié)合臨床特征可顯著提高預(yù)測(cè)準(zhǔn)確率(AUC=0.86)。

1.2 KRAS基因突變與CT特征 KRAS基因突變最常發(fā)生于2、3外顯子，多見于腺癌，白種人突變率約為25%～50%，亞洲人群突變率約5%～15%，好發(fā)于吸煙者[20]。KRAS突變目前尚無(wú)特異性靶向治療藥物，其與影像特征相關(guān)性的研究較少，部分研究[9]未發(fā)現(xiàn)KRAS突變的影像標(biāo)志物。Sugano等[10]研究顯示KRAS突變更常見于最大徑≥31 mm的腫瘤(P=0.003)。筆者前期[21]研究手術(shù)病理證實(shí)的Ⅰ期肺腺癌患者的CT特征與KRAS突變的關(guān)系，發(fā)現(xiàn)毛刺征與KRAS突變相關(guān)(優(yōu)勢(shì)比2.99)。Rizzo等[7]研究發(fā)現(xiàn)圓形病灶(優(yōu)勢(shì)比2.40)和非腫瘤所在肺葉結(jié)節(jié)(優(yōu)勢(shì)比1.89)與KRAS突變相關(guān)。Wang等[22]認(rèn)為ⅠA期肺腺癌中GGO比例小者更常出現(xiàn)KRAS突變 (P=0.018)。

在影像基因組學(xué)領(lǐng)域，Weiss等[23]研究KRAS突變型與野生型(26種基因突變檢測(cè)均陰性)早期NSCLC紋理特征差別，發(fā)現(xiàn)精細(xì)紋理的陽(yáng)性偏度(P=0.031)和粗糙紋理的較低峰度(P=0.009)與KRAS突變相關(guān)。前述Rios Velazquez等[19]的研究發(fā)現(xiàn)10個(gè)特征與KRAS突變相關(guān)，這些特征提示存在KRAS突變的腫瘤更均質(zhì)。影像組學(xué)特征可區(qū)分KRAS陽(yáng)性與KRAS陰性，但預(yù)測(cè)效能有限(AUC=0.63)，且結(jié)合臨床特征后并不能提高臨床特征的預(yù)測(cè)準(zhǔn)確率(AUC=0.69)。

1.3 ALK基因重排與CT特征 ALK基因重排中，EML4和ALK融合(EML4-ALK)最常見，多見于肺腺癌，發(fā)生率約4%，好發(fā)于年輕不吸煙或輕度吸煙者[24]?？诉蛱婺崾且环N小分子ATP競(jìng)爭(zhēng)性酪氨酸激酶抑制劑，除ALK外，還具有c-MET和ROS1靶點(diǎn)[24]，于2011年獲得美國(guó)食品與藥品監(jiān)督管理局批準(zhǔn)，2013年在中國(guó)獲批上市。研究[25-26]報(bào)道存在ALK重排的NSCLC多為無(wú)GGO成分的實(shí)性腫瘤。也有研究[27]顯示ALK重排相關(guān)的CT特征為腫瘤位于鎖骨中線內(nèi)側(cè)、無(wú)胸膜尾征及伴大量胸腔積液。ALK重排與EGFR突變NSCLC的臨床特征相似，均好發(fā)于年輕不吸煙者，因此研究者們?cè)噲D探尋二者之間影像特征的差異。已有研究[28-30]結(jié)果顯示，相比于存在EGFR突變的腫瘤，ALK重排腫瘤更傾向于實(shí)性、無(wú)或少GGO成分，伴多發(fā)淋巴結(jié)腫大[30-32]，尤其是N分期較晚的淋巴結(jié)腫大。更常見于ALK重排的腫瘤的CT特征還包括增強(qiáng)時(shí)CT值較低[29]、癌性淋巴管炎[32]等。有些研究結(jié)果甚至相互矛盾，如Kim等[29]和Choi等[32]發(fā)現(xiàn)ALK重排腫瘤邊緣多分葉，而Zhou等[28]的研究發(fā)現(xiàn)分葉狀邊緣更常見于存在EGFR突變的腫瘤。

融合陽(yáng)性肺腺癌的影像特征為近年來(lái)此領(lǐng)域研究的新興趣點(diǎn)。Yoon等[33]觀察ALK、ROS1和RET陽(yáng)性肺腺癌的臨床特征和包括定性、定量CT及PET/CT特征的影像組學(xué)特征，發(fā)現(xiàn)相比于ROS1或RET陽(yáng)性的肺腺癌，ALK重排腫瘤分期更晚(P=0.042)，多位于鎖骨中線內(nèi)側(cè)(P=0.017)，最大標(biāo)準(zhǔn)攝取值(standardized uptake value，SUVmax)更高(P=0.005)，1、2、3體素距離的均勻度更高(P=0.030、0.023、0.028)，2體素距離的均值和更大(P=0.049)。

1.4 其他驅(qū)動(dòng)基因突變與CT特征 由于突變率低或缺乏特異性靶向治療藥物等原因，NSCLC其他驅(qū)動(dòng)基因突變相關(guān)影像特征的研究罕見。ROS1和RET重排均分別占肺腺癌的1%～2%[34]。Plodkowski等[35]研究ROS1和RET重排肺腺癌的CT特征，認(rèn)為ROS1重排組較EGFR突變組腫瘤更好發(fā)于肺外周部(P=0.04)，而RET重排組與EGFR突變組CT特征間無(wú)明顯差異。BRAF突變占NSCLC的2%～5%[36]，Halpenny等[37]研究了BRAF突變肺癌的影像特征，結(jié)果顯示BRAF突變組與非突變組原發(fā)腫瘤的CT特征無(wú)顯著性差異，BRAF突變組較KRAS突變組更易出現(xiàn)胸腔積液(P=0.033)和胸膜轉(zhuǎn)移 (P=0.045)。

2 NSCLC影像基因組學(xué)面臨的挑戰(zhàn)和機(jī)遇

NSCLC影像學(xué)特征與分子表型間存在內(nèi)在聯(lián)系，CT特征對(duì)預(yù)測(cè)基因突變有一定提示作用。但影像基因組學(xué)研究尚處于初始階段，各研究間結(jié)論尚不統(tǒng)一。造成這種現(xiàn)象的原因可能是大多數(shù)研究為回顧性分析，樣本量相差較大，病例構(gòu)成比即性別、年齡、種族、吸煙狀態(tài)、組織學(xué)類型及分期不同，基因突變檢測(cè)方法各異等。傳統(tǒng)影像學(xué)定性評(píng)價(jià)存在缺乏統(tǒng)一評(píng)價(jià)標(biāo)準(zhǔn)、受閱片者經(jīng)驗(yàn)等主觀因素影響的問(wèn)題，而計(jì)算機(jī)提取定量特征的影像組學(xué)研究也存在諸多問(wèn)題，如數(shù)據(jù)采集方面受設(shè)備、掃描參數(shù)和是否使用對(duì)比劑的影響，腫瘤分割、特征提取篩選及預(yù)測(cè)模型建立方面尚缺乏規(guī)范化、標(biāo)準(zhǔn)化的流程和質(zhì)量控制體系[38]。雖然增加影像組學(xué)特征可提高對(duì)EGFR突變的預(yù)測(cè)效能，但其本身的預(yù)測(cè)效能并不優(yōu)于臨床特征[17-19]；而即使增加影像組學(xué)特征也不能提高對(duì)KRAS突變的預(yù)測(cè)效能[19]。未來(lái)還需要通過(guò)多專業(yè)合作、多中心研究，實(shí)現(xiàn)數(shù)據(jù)共享，優(yōu)化影像組學(xué)流程和算法，共同努力提高預(yù)測(cè)基因突變的準(zhǔn)確率，從而在制定臨床決策和精準(zhǔn)醫(yī)療中發(fā)揮更大作用。

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