肺癌患者吸煙與p53基因突變關聯性的Meta分析

林雪君,顏康康,趙龍宇,鮑紅紅,李 雙,劉曉冬,劉 欣

(1.吉林大學公共衛生學院流行病與衛生統計學教研室,吉林長春130021;2.吉林大學公共衛生學院衛生部放射生物學重點實驗室,吉林長春 130021)

肺癌患者吸煙與p53基因突變關聯性的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.吉林大學公共衛生學院流行病與衛生統計學教研室,吉林長春130021;2.吉林大學公共衛生學院衛生部放射生物學重點實驗室,吉林長春 130021)

目的:采用Meta分析的方法綜合評價肺癌患者吸煙與p53基因突變的關聯性。方法:全面檢索Pub Med、Web of Science、Pro Quest和Medline數據庫,收集有關肺癌患者吸煙與p53基因突變關系研究的文獻。在全面文獻回顧的基礎上對文獻進行篩選、評價和數據提取。采用Stata 12.0軟件對納入文獻進行Meta分析,包括異質性檢驗、評估文獻發表偏倚、敏感性分析、合并效應量及累積Meta分析。結果:本研究共納入15篇文獻,包含1 770名肺癌患者,其中69.6%為吸煙者,30.4%為非吸煙者。異質性檢驗未發現各研究間存在明顯異質性。肺癌患者吸煙與p53基因突變關系的合并OR＝2.70,95%CI＝2.04～3.59。結論:肺癌患者吸煙與p53基因突變有關聯性;與非吸煙者比較,吸煙者的p53基因突變風險高。

肺腫瘤;吸煙;p53基因突變;Meta分析

近年來,肺癌死亡率穩居癌癥之首[1]。據美國癌癥協會報道,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50年代以來,大量流行病學證據[4-5]顯示:長期過量地使用煙草已成為肺癌的確定性危險因素,87%的肺癌由吸煙引起。同時,肺癌患者中p53基因的突變表達很普遍,在非小細胞肺癌(non-small cell lung cancer,NSCLC)中p53突變率可達到50%,而在小細胞肺癌(small cell lung cancer,SCLC)中p53突變率更高,可達80%[6]。到目前為止,盡管已有流行病學研究在肺癌人群中探索了吸煙與p53基因突變間的關系,但仍有一些局限性,如只在單一肺癌組織學類型、單一性別和特定地區人群中研究等,從而使結果在一定程度上存在不確定性。因此,有必要進行全面的Meta分析,以期獲得肺癌人群中吸煙與p53基因突變是否相關的確切結論。而在此領域,僅于2011年Ma等[7]進行了NSCLC p53基因突變與吸煙相關性的Meta分析研究。本文作者收集了近20年來多篇高質量文獻,在多種肺癌組織學類型中探討吸煙與p53基因突變的關聯性。

1 資料與方法

1.1 檢索策略以“lung cancer”、“lung neoplasm”、“lung carcinoma”、“p53 mutation”和“smoking”為關鍵詞聯合檢索Pub Med、Web of Science、ProQuest和Medline數據庫公開發表的相關文獻,檢索時間為1992年1月—2012年9月。

1.2 納入與排除標準納入標準:①已發表的英文文獻;②研究對象為肺癌患者且病例須經病理組織學確診;③基因突變是通過檢測經手術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吸煙者,非吸煙者定義為一生中吸煙支數少于100支者;⑤文獻必須提供有關吸煙組和非吸煙組中p53基因突變個體數量的信息。排除標準:①綜述類文獻;②數據資料不完整;③文獻質量較差;④各種原因無法獲得全文;⑤對于相同數據來源的重復報道,選用最新近報道或最大樣本量的研究,其余文獻均排除。

1.3 質量控制本研究采用紐卡斯爾-渥太華量表(Newcastle-Ottawa Scale,NOS)對可能納入的文獻進行質量評分,評價內容包括3大塊共8個條目,即研究對象選擇4個條目(4分)、組間可比性1個條目(2分)、暴露因素或結果測量3個條目(3分),滿分為9分;6分以上定為較高質量文獻[8]。文獻的質量評價及數據提取均由2位審閱人獨立進行,當2位審閱人意見不同時,需通過討論或引入第3位審閱人解決。

1.4 統計學分析采用Stata 12.0軟件對肺癌患者吸煙與p53基因突變的關聯強度進行統計學分析,計算各研究的效應指標比值比(odds ratios, OR)及其95%可信區間(95%CI)。在合并效應量前需進行異質性檢驗。當異質性檢驗結果為P＞0.10且I2≤50%時,可認為多個同類研究間具有同質性,選用固定效應模型計算合并效應量;當P≤0.10且I2＞50%時,可認為多個研究間有異質性,選用隨機效應模型計算合并效應量。對于研究中非吸煙組中無突變個體的情況,即研究中吸煙組的p53基因突變個體、不突變個體,非吸煙組的p53基因突變個體、不突變個體4個格子中有1個無數值,那么此時應給每個格子的數值加0.5,軟件會自動校正所有格子中的數值進行分析[9]。

2 結果

2.1 納入文獻的基本情況按照上述檢索策略共檢索到294篇文獻,經閱讀標題和摘要后,排除與p53基因突變和肺癌無關的文獻225篇,剩余69篇;經閱讀全文后,排除綜述、重復發表、研究對象不是人類及無詳細吸煙史信息的文獻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體信息的文獻16篇,剩余15篇。嚴格按照如上篩選流程及納入標準,最終本次Meta分析共納入15篇文獻[10-24]。在納入的15篇文獻中,有8篇被評為6分,7篇被評為7分,納入文獻質量較高。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。納入文獻的基本情況見表1。

2.2 Meta分析結果本組納入的各研究具有統計學同質性(I2＝21.30%,P＝0.217),采用固定效應模型進行合并分析,肺癌患者中吸煙人群p53基因突變風險是非吸煙人群的2.7倍(OR＝2.70, 95%CI＝2.04～3.59)。見圖1。

表1 納入文獻的基本情況及質量評價結果Tab.1 Main characteristics and NOS scores of included studies

圖1 肺癌患者吸煙與p53基因突變關聯性的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 發表偏倚應用Begg’s漏斗圖和Egger’s檢驗評價納入文獻是否存在發表偏倚。Begg’s漏斗圖無明顯不對稱,同時Egger’s檢驗P＝0.426 (P＞0.05),提示本研究納入文獻無發表偏倚。見圖2。

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

圖2 肺癌患者吸煙與p53基因突變關聯性的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按研究時間次序及時進行新的Meta分析的過程。隨著文獻數量的逐漸增加,可以進一步反映研究結果的動態變化趨勢。按年代先后順序累積Meta分析后,OR估計值及95%可信區間趨于穩定,且可信區間的范圍逐漸縮窄,從而增加了總體效應量估計的準確性。見圖3。

圖3 肺癌患者吸煙與p53基因突變關聯性的累積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因素之一。已有研究[25]表明:吸煙與p53基因突變風險間存在線性相關關系。吸煙越多,肺癌患者p53突變率越高[11]。同時,與其他癌癥比較,肺癌的p53突變率相對更高。

癌癥的發生、發展是一個原癌基因激活和抑癌基因失活共同參與的復雜過程。煙草燃燒中產生的苯并(a)芘(BaP)已被國際癌癥研究機構(IARC)列為Ⅰ類致癌物(人類已知的)。BaP經色素P450(CYP)酶催化后代謝活化,導致一些BaP代謝物與DNA共價結合,從而形成DNA加合物。如果這些DNA加合物未被修復,將導致腫瘤抑制基因或激活基因發生突變[26]。p53基因是定位于17號染色體短臂上的抑癌基因,野生型p53基因通過阻滯細胞周期于G0/G1期而抑制細胞增殖,若p53基因發生突變則喪失這一作用而引起致瘤性轉化[13]。煙草中的致癌物已經被證實可直接導致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顛換突變為主,而非吸煙的肺癌患者以G到A顛換突變為主[14,27]。國外許多流行病學研究已經證實肺癌患者中吸煙與p53基因突變間存在關系。Vahakangas等[18]對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%,曾經吸煙者p53突變率為67%,曾經吸煙者p53突變率高于非吸煙者,差異有統計學意義(P＝0.016)。

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

綜上所述,本組Meta分析中異質性檢驗表明納入的15個研究間無異質性;Begg’s漏斗圖對稱性良好,Egger’s檢驗P＝0.426,均提示納入文獻無發表偏倚;敏感性分析剔除3篇文獻前后結論未發生明顯變化。以上結果保證了本次Meta分析及累積Meta分析的結果穩定可靠。提示在肺癌患者中,吸煙與p53基因突變的風險有關聯;與非吸煙者比較,吸煙者的p53基因突變風險高。

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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);吉林大學白求恩醫學部醫學科研支持計劃青年科研基金資助課題(2013202013)

林雪君(1989－),女,吉林省敦化市人,在讀醫學碩士,主要從事醫學統計學研究。

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

1671-587Ⅹ(2014)05-1046-05

10.13481/j.1671-587x.20140527