林雪君,顏康康,趙龍宇,鮑紅紅,李 雙,劉曉冬,劉 欣

(1.吉林大學(xué)公共衛(wèi)生學(xué)院流行病與衛(wèi)生統(tǒng)計(jì)學(xué)教研室,吉林長(zhǎng)春130021;2.吉林大學(xué)公共衛(wèi)生學(xué)院衛(wèi)生部放射生物學(xué)重點(diǎn)實(shí)驗(yàn)室,吉林長(zhǎng)春 130021)

肺癌患者吸煙與p53基因突變關(guān)聯(lián)性的Meta分析

林雪君1,顏康康1,趙龍宇1,鮑紅紅1,李 雙1,劉曉冬2,劉 欣1

(1.吉林大學(xué)公共衛(wèi)生學(xué)院流行病與衛(wèi)生統(tǒng)計(jì)學(xué)教研室,吉林長(zhǎng)春130021;2.吉林大學(xué)公共衛(wèi)生學(xué)院衛(wèi)生部放射生物學(xué)重點(diǎn)實(shí)驗(yàn)室,吉林長(zhǎng)春 130021)

目的:采用Meta分析的方法綜合評(píng)價(jià)肺癌患者吸煙與p53基因突變的關(guān)聯(lián)性。方法:全面檢索Pub Med、Web of Science、Pro Quest和Medline數(shù)據(jù)庫,收集有關(guān)肺癌患者吸煙與p53基因突變關(guān)系研究的文獻(xiàn)。在全面文獻(xiàn)回顧的基礎(chǔ)上對(duì)文獻(xiàn)進(jìn)行篩選、評(píng)價(jià)和數(shù)據(jù)提取。采用Stata 12.0軟件對(duì)納入文獻(xiàn)進(jìn)行Meta分析,包括異質(zhì)性檢驗(yàn)、評(píng)估文獻(xiàn)發(fā)表偏倚、敏感性分析、合并效應(yīng)量及累積Meta分析。結(jié)果:本研究共納入15篇文獻(xiàn),包含1 770名肺癌患者,其中69.6%為吸煙者,30.4%為非吸煙者。異質(zhì)性檢驗(yàn)未發(fā)現(xiàn)各研究間存在明顯異質(zhì)性。肺癌患者吸煙與p53基因突變關(guān)系的合并OR＝2.70,95%CI＝2.04～3.59。結(jié)論:肺癌患者吸煙與p53基因突變有關(guān)聯(lián)性;與非吸煙者比較,吸煙者的p53基因突變風(fēng)險(xiǎn)高。

肺腫瘤;吸煙;p53基因突變;Meta分析

近年來,肺癌死亡率穩(wěn)居癌癥之首[1]。據(jù)美國(guó)癌癥協(xié)會(huì)報(bào)道,早在1987年,女性肺癌已超過乳腺癌位居癌癥死亡原因之首[2]。2013年,肺癌占女性癌癥死亡原因的26%[3]。自20世紀(jì)50年代以來,大量流行病學(xué)證據(jù)[4-5]顯示:長(zhǎng)期過量地使用煙草已成為肺癌的確定性危險(xiǎn)因素,87%的肺癌由吸煙引起。同時(shí),肺癌患者中p53基因的突變表達(dá)很普遍,在非小細(xì)胞肺癌(non-small cell lung cancer,NSCLC)中p53突變率可達(dá)到50%,而在小細(xì)胞肺癌(small cell lung cancer,SCLC)中p53突變率更高,可達(dá)80%[6]。到目前為止,盡管已有流行病學(xué)研究在肺癌人群中探索了吸煙與p53基因突變間的關(guān)系,但仍有一些局限性,如只在單一肺癌組織學(xué)類型、單一性別和特定地區(qū)人群中研究等,從而使結(jié)果在一定程度上存在不確定性。因此,有必要進(jìn)行全面的Meta分析,以期獲得肺癌人群中吸煙與p53基因突變是否相關(guān)的確切結(jié)論。而在此領(lǐng)域,僅于2011年Ma等[7]進(jìn)行了NSCLC p53基因突變與吸煙相關(guān)性的Meta分析研究。本文作者收集了近20年來多篇高質(zhì)量文獻(xiàn),在多種肺癌組織學(xué)類型中探討吸煙與p53基因突變的關(guān)聯(lián)性。

1 資料與方法

1.1 檢索策略以“l(fā)ung cancer”、“l(fā)ung neoplasm”、“l(fā)ung carcinoma”、“p53 mutation”和“smoking”為關(guān)鍵詞聯(lián)合檢索Pub Med、Web of Science、ProQuest和Medline數(shù)據(jù)庫公開發(fā)表的相關(guān)文獻(xiàn),檢索時(shí)間為1992年1月—2012年9月。

1.2 納入與排除標(biāo)準(zhǔn)納入標(biāo)準(zhǔn):①已發(fā)表的英文文獻(xiàn);②研究對(duì)象為肺癌患者且病例須經(jīng)病理組織學(xué)確診;③基因突變是通過檢測(cè)經(jīng)手術(shù)或活檢得到的腫瘤組織確定;④吸煙者包括正在吸煙者和曾經(jīng)吸煙者,非吸煙者定義為一生中吸煙支數(shù)少于100支者;⑤文獻(xiàn)必須提供有關(guān)吸煙組和非吸煙組中p53基因突變個(gè)體數(shù)量的信息。排除標(biāo)準(zhǔn):①綜述類文獻(xiàn);②數(shù)據(jù)資料不完整;③文獻(xiàn)質(zhì)量較差;④各種原因無法獲得全文;⑤對(duì)于相同數(shù)據(jù)來源的重復(fù)報(bào)道,選用最新近報(bào)道或最大樣本量的研究,其余文獻(xiàn)均排除。

1.3 質(zhì)量控制本研究采用紐卡斯?fàn)?渥太華量表(Newcastle-Ottawa Scale,NOS)對(duì)可能納入的文獻(xiàn)進(jìn)行質(zhì)量評(píng)分,評(píng)價(jià)內(nèi)容包括3大塊共8個(gè)條目,即研究對(duì)象選擇4個(gè)條目(4分)、組間可比性1個(gè)條目(2分)、暴露因素或結(jié)果測(cè)量3個(gè)條目(3分),滿分為9分;6分以上定為較高質(zhì)量文獻(xiàn)[8]。文獻(xiàn)的質(zhì)量評(píng)價(jià)及數(shù)據(jù)提取均由2位審閱人獨(dú)立進(jìn)行,當(dāng)2位審閱人意見不同時(shí),需通過討論或引入第3位審閱人解決。

1.4 統(tǒng)計(jì)學(xué)分析采用Stata 12.0軟件對(duì)肺癌患者吸煙與p53基因突變的關(guān)聯(lián)強(qiáng)度進(jìn)行統(tǒng)計(jì)學(xué)分析,計(jì)算各研究的效應(yīng)指標(biāo)比值比(odds ratios, OR)及其95%可信區(qū)間(95%CI)。在合并效應(yīng)量前需進(jìn)行異質(zhì)性檢驗(yàn)。當(dāng)異質(zhì)性檢驗(yàn)結(jié)果為P＞0.10且I2≤50%時(shí),可認(rèn)為多個(gè)同類研究間具有同質(zhì)性,選用固定效應(yīng)模型計(jì)算合并效應(yīng)量;當(dāng)P≤0.10且I2＞50%時(shí),可認(rèn)為多個(gè)研究間有異質(zhì)性,選用隨機(jī)效應(yīng)模型計(jì)算合并效應(yīng)量。對(duì)于研究中非吸煙組中無突變個(gè)體的情況,即研究中吸煙組的p53基因突變個(gè)體、不突變個(gè)體,非吸煙組的p53基因突變個(gè)體、不突變個(gè)體4個(gè)格子中有1個(gè)無數(shù)值,那么此時(shí)應(yīng)給每個(gè)格子的數(shù)值加0.5,軟件會(huì)自動(dòng)校正所有格子中的數(shù)值進(jìn)行分析[9]。

2 結(jié)果

2.1 納入文獻(xiàn)的基本情況按照上述檢索策略共檢索到294篇文獻(xiàn),經(jīng)閱讀標(biāo)題和摘要后,排除與p53基因突變和肺癌無關(guān)的文獻(xiàn)225篇,剩余69篇;經(jīng)閱讀全文后,排除綜述、重復(fù)發(fā)表、研究對(duì)象不是人類及無詳細(xì)吸煙史信息的文獻(xiàn)38篇,剩余31篇;排除未明確提供吸煙組或非吸煙組p53基因突變及不突變個(gè)體信息的文獻(xiàn)16篇,剩余15篇。嚴(yán)格按照如上篩選流程及納入標(biāo)準(zhǔn),最終本次Meta分析共納入15篇文獻(xiàn)[10-24]。在納入的15篇文獻(xiàn)中,有8篇被評(píng)為6分,7篇被評(píng)為7分,納入文獻(xiàn)質(zhì)量較高。見表1。

本次Meta分析共有1 770名肺癌患者,其中1 232名患者為吸煙者,占69.6%;538名患者為非吸煙者,占30.4%。吸煙組患者p53突變率最低為17.1%,最高達(dá)67.5%;而非吸煙組患者p53突變率最高為39.4%,提示患肺癌的吸煙人群p53基因突變率高于非吸煙人群。納入文獻(xiàn)的基本情況見表1。

2.2 Meta分析結(jié)果本組納入的各研究具有統(tǒng)計(jì)學(xué)同質(zhì)性(I2＝21.30%,P＝0.217),采用固定效應(yīng)模型進(jìn)行合并分析,肺癌患者中吸煙人群p53基因突變風(fēng)險(xiǎn)是非吸煙人群的2.7倍(OR＝2.70, 95%CI＝2.04～3.59)。見圖1。

表1 納入文獻(xiàn)的基本情況及質(zhì)量評(píng)價(jià)結(jié)果Tab.1 Main characteristics and NOS scores of included studies

圖1 肺癌患者吸煙與p53基因突變關(guān)聯(lián)性的Meta分析森林圖Fig.1 Forest plot of Meta-analysis on association between smoking and p53 mutation in patients with lung cancer

2.3 發(fā)表偏倚應(yīng)用Begg’s漏斗圖和Egger’s檢驗(yàn)評(píng)價(jià)納入文獻(xiàn)是否存在發(fā)表偏倚。Begg’s漏斗圖無明顯不對(duì)稱,同時(shí)Egger’s檢驗(yàn)P＝0.426 (P＞0.05),提示本研究納入文獻(xiàn)無發(fā)表偏倚。見圖2。

2.4 敏感性分析敏感性分析是用于評(píng)價(jià)Meta分析結(jié)果是否穩(wěn)定和可靠的方法。當(dāng)本文作者排除樣本量小且非吸煙人群中無突變個(gè)體的3篇文獻(xiàn)[10,13,21]后,剩下的12篇文獻(xiàn)的合并OR值為2.66(OR＝2.66,95%CI＝2.00～3.55),合并效應(yīng)量在剔除3篇文獻(xiàn)前后,未發(fā)生明顯變化,結(jié)論無改變。由此可知,本研究結(jié)果穩(wěn)定可靠。

圖2 肺癌患者吸煙與p53基因突變關(guān)聯(lián)性的Meta分析漏斗圖Fig.2 Funnel plot of Meta-analysis on association between smoking and p53 mutation in patients with lung cancer

2.5 累積Meta分析累積Meta分析是將納入的文獻(xiàn)按研究時(shí)間次序及時(shí)進(jìn)行新的Meta分析的過程。隨著文獻(xiàn)數(shù)量的逐漸增加,可以進(jìn)一步反映研究結(jié)果的動(dòng)態(tài)變化趨勢(shì)。按年代先后順序累積Meta分析后,OR估計(jì)值及95%可信區(qū)間趨于穩(wěn)定,且可信區(qū)間的范圍逐漸縮窄,從而增加了總體效應(yīng)量估計(jì)的準(zhǔn)確性。見圖3。

圖3 肺癌患者吸煙與p53基因突變關(guān)聯(lián)性的累積Meta分析森林圖Fig.3 Forest plot of cumulative Meta-analysis on association between smoking and p53 mutation in patients with lung cancer

3 討 論

吸煙是引起肺癌最重要的危險(xiǎn)因素之一。已有研究[25]表明:吸煙與p53基因突變風(fēng)險(xiǎn)間存在線性相關(guān)關(guān)系。吸煙越多,肺癌患者p53突變率越高[11]。同時(shí),與其他癌癥比較,肺癌的p53突變率相對(duì)更高。

癌癥的發(fā)生、發(fā)展是一個(gè)原癌基因激活和抑癌基因失活共同參與的復(fù)雜過程。煙草燃燒中產(chǎn)生的苯并(a)芘(BaP)已被國(guó)際癌癥研究機(jī)構(gòu)(IARC)列為Ⅰ類致癌物(人類已知的)。BaP經(jīng)色素P450(CYP)酶催化后代謝活化,導(dǎo)致一些BaP代謝物與DNA共價(jià)結(jié)合,從而形成DNA加合物。如果這些DNA加合物未被修復(fù),將導(dǎo)致腫瘤抑制基因或激活基因發(fā)生突變[26]。p53基因是定位于17號(hào)染色體短臂上的抑癌基因,野生型p53基因通過阻滯細(xì)胞周期于G0/G1期而抑制細(xì)胞增殖,若p53基因發(fā)生突變則喪失這一作用而引起致瘤性轉(zhuǎn)化[13]。煙草中的致癌物已經(jīng)被證實(shí)可直接導(dǎo)致p53基因突變,其中吸煙與不吸煙肺癌患者的p53突變譜不同。吸煙的肺癌患者以G到T顛換突變?yōu)橹?而非吸煙的肺癌患者以G到A顛換突變?yōu)橹鱗14,27]。國(guó)外許多流行病學(xué)研究已經(jīng)證實(shí)肺癌患者中吸煙與p53基因突變間存在關(guān)系。Vahakangas等[18]對(duì)131例高加索女性肺癌患者的研究表明:非吸煙者p53突變率為19%,曾經(jīng)吸煙者p53突變率為67%,曾經(jīng)吸煙者p53突變率高于非吸煙者,差異有統(tǒng)計(jì)學(xué)意義(P＝0.016)。

另外,Devi等[28]在對(duì)印度南部的肺癌病例研究中發(fā)現(xiàn):大量吸煙可提高p53基因突變的風(fēng)險(xiǎn)。Anna等[29]在匈牙利肺癌患者中發(fā)現(xiàn):p53突變率與煙齡有關(guān),吸煙者的DNA加合物水平是曾經(jīng)吸煙及非吸煙者的2倍。本研究結(jié)果顯示:患肺癌的吸煙者p53基因突變率較非吸煙者高;吸煙人群p53基因突變風(fēng)險(xiǎn)是非吸煙人群的2.7倍。這與上述研究結(jié)論一致。

綜上所述,本組Meta分析中異質(zhì)性檢驗(yàn)表明納入的15個(gè)研究間無異質(zhì)性;Begg’s漏斗圖對(duì)稱性良好,Egger’s檢驗(yàn)P＝0.426,均提示納入文獻(xiàn)無發(fā)表偏倚;敏感性分析剔除3篇文獻(xiàn)前后結(jié)論未發(fā)生明顯變化。以上結(jié)果保證了本次Meta分析及累積Meta分析的結(jié)果穩(wěn)定可靠。提示在肺癌患者中,吸煙與p53基因突變的風(fēng)險(xiǎn)有關(guān)聯(lián);與非吸煙者比較,吸煙者的p53基因突變風(fēng)險(xiǎn)高。

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Meta-analysis on association between smoking and p53 gene mutation in patients with lung cancer

LIN Xue-jun1,YAN Kang-kang1,ZHAO Long-yu1,BAO Hong-hong1,LI Shuang1,LIU Xiao-dong2,LIU Xin1
(1.Department of Epidemiology and Health Statistics,School of Public Health,Jilin University, Changchun 130021,China;2.Key Laboratory of Radiobiology,Ministry of Health,School of Public Health,Jilin University,Changchun 130021,China)

ObjectiveTo evaluate the relationship between smoking and p53 gene mutation in the lung cancer patients with Meta-analysis.MethodsPub Med,Web of Science,ProQest and Medline were used to search all the relevant studies about the association between smoking and p53 gene mutation in the patients with lung cancer.Based on reviewing full text,the studies were selected and evaluated and the data was extracted.Statistical analysis was performed with Stata 12.0 software including the heterogeneity inspection,publication bias assessment, sensitivity analysis,effect consolidating and cumulative Meta-analysis.ResultsTotally 15 articles with 1 770 lung cancer patients were identified.69.6%of the patients were smokers,30.4%were non-smokers.Overall,the smokers with lung cancer had a 2.70-fold higher risk for p53 gene mutation than the non-smokers with lung cancer (OR＝2.70,95%CI＝2.04－3.59).Conclusionp53 gene mutation is associated with smoking in the patients with lung cancer.The smokers with lung cancer have higher risk for p53 mutation than non-smokers.

lung neoplasms;smoking;p53 gene mutation;Meta-analysis

R734.2

A

2013-10-31

吉林省科技廳科研基金資助課題(201205008);吉林大學(xué)白求恩醫(yī)學(xué)部醫(yī)學(xué)科研支持計(jì)劃青年科研基金資助課題(2013202013)

林雪君(1989－),女,吉林省敦化市人,在讀醫(yī)學(xué)碩士,主要從事醫(yī)學(xué)統(tǒng)計(jì)學(xué)研究。

劉 欣(Tel:0431-85619431,E-mail:xliu＠jlu.edu.cn)

1671-587Ⅹ(2014)05-1046-05

10.13481/j.1671-587x.20140527