武亞運(yùn)，董曉強(qiáng)，王勇攀，王進(jìn)，張志，毛德利，何宋兵

（1.浙江省嘉善縣第一人民醫(yī)院 普通外科，浙江 嘉善 314100；2.蘇州大學(xué)附屬第一醫(yī)院 普通外科，江蘇 蘇州 215006）

WHO早已宣布乳腺癌是女性群體中最常見的惡性腫瘤[1]，根據(jù)文獻(xiàn)[2]報(bào)道，2012年全球有新發(fā)乳腺癌患者約167.66萬例，因乳腺癌死亡患者約52.19萬例。對(duì)于我國(guó)而言，近年來乳腺癌患者的發(fā)病率上升趨勢(shì)顯著，而病死率則趨于相對(duì)穩(wěn)定[3]，可能是因?yàn)榻陙砼曰颊吣軌蜃龅郊皶r(shí)篩查，早期發(fā)現(xiàn)，對(duì)疾病認(rèn)識(shí)及治療水平的提高，但是總體來說，其預(yù)后仍處于較差水平，根據(jù)發(fā)展中國(guó)家的統(tǒng)計(jì)結(jié)果顯示，乳腺癌患者的5年生存率處于50%～60%范圍之內(nèi)[4]。乳腺癌的發(fā)生其實(shí)是一個(gè)包含多重步驟的進(jìn)程，在這個(gè)進(jìn)程中有多個(gè)因子的參與，尤其是基因的突變，其在乳腺癌的發(fā)展過程中擔(dān)當(dāng)著不容忽視的角色。鼠雙微體基因（murine double minute 2，MDM-2）是1991年從BALB/3T3DM細(xì)胞中克隆出來的一種高度擴(kuò)增基因[5]，其定位于染色體12q14.3～q15，包含2個(gè)轉(zhuǎn)錄啟動(dòng)子序列P1和P2，其轉(zhuǎn)錄產(chǎn)物為包含5.5 kb的mRNA[6]，編碼491個(gè)氨基酸，其作為p53功能的負(fù)性調(diào)節(jié)因子，是p53信號(hào)途徑的重要組成部分[7-8]，與腫瘤的發(fā)生有密不可分的聯(lián)系。本研究通過數(shù)據(jù)庫檢索，Meta分析的方式，對(duì)MDM-2基因rs2279744位點(diǎn)多態(tài)性與乳腺癌的發(fā)病風(fēng)險(xiǎn)進(jìn)行評(píng)價(jià)。

1 資料與方法

1.1 研究的引入和剔除

1.1.1 文獻(xiàn)類型 ⑴ 病例對(duì)照研究；⑵ 數(shù)據(jù)完整、可信度高；⑶ 無國(guó)別及語種限制；⑷ 對(duì)外公開的文獻(xiàn)或研究。

1.1.2 研究個(gè)體 病例組均為罹患乳腺癌個(gè)體，對(duì)照組均為未罹患乳腺癌的個(gè)體（社區(qū)對(duì)照與醫(yī)院對(duì)照均包含在內(nèi)）。

1.1.3 分析因素 MDM2基因rs2279744位點(diǎn)的突變。

1.1.4 可評(píng)價(jià)指標(biāo) rs2279744位點(diǎn)突變型與非突變型在病例與對(duì)照中的比例。

1.1.5 剔除 ⑴ 會(huì)議論文或摘要，綜述以及系統(tǒng)評(píng)價(jià)類文獻(xiàn)；⑵ 中文類碩士學(xué)位論文；⑶ 動(dòng)物實(shí)驗(yàn)；⑷ 二次研究。

1.2 文獻(xiàn)檢索策略

檢索的中文數(shù)據(jù)庫包括CBM、WANFANG、及CNKI；英文數(shù)據(jù)庫包括Pubmed、Embase、Web of Science。檢索時(shí)間均為建庫至至2017年7月1日。檢索無國(guó)別及語種限制。英文檢索詞包括：breast neoplasm、breast tumor、mammary carcinoma、breast carcinoma、mammary neoplasm、breast cancer、polymorphism、SNP、SNPs、variant、mutation、c-mdm2、mdm-2、mdm2、protooncogene proteins c-mdm2、snp309、309、rs2279744、t-g、t309g；中文檢索詞包括：乳腺癌、乳腺腫瘤、乳腺惡性腫瘤、乳癌、乳房癌、多態(tài)性、多態(tài)型、多型性、MDM2、雙微體。

1.3 篩選和資料提取

研究的篩選由多名人員完成（n≥3）。主要提取的信息包括：年份、樣本量、研究設(shè)計(jì)類型、測(cè)序及基因分型技術(shù)、突變與野生型比例等方面內(nèi)容。

1.4 文獻(xiàn)質(zhì)量及風(fēng)險(xiǎn)評(píng)價(jià)

此次Meta分析，由于納入的所有研究類型均為病例-對(duì)照研究，選用NOS量表進(jìn)行質(zhì)量評(píng)價(jià)，以其下包含的8個(gè)分支小條目作為評(píng)分點(diǎn)。高于6分（含6分）的研究才可進(jìn)行Meta分析。經(jīng)評(píng)價(jià)后所有入選文獻(xiàn)評(píng)分均在6分及6分以上。

1.5 統(tǒng)計(jì)學(xué)處理

用Stata 14.0對(duì)數(shù)據(jù)進(jìn)行處理，首先是對(duì)照組進(jìn)行HWE平衡檢測(cè)，P＞0.05方可認(rèn)為對(duì)照組處于HWE平衡狀態(tài)，對(duì)包含的研究應(yīng)用χ2進(jìn)行異質(zhì)性檢驗(yàn)分析，I2＜50%且P＞0.05才表明各個(gè)研究之間不存在明顯異質(zhì)性，配合固定效應(yīng)模型進(jìn)行分析，否則配合隨機(jī)效應(yīng)模型分析。對(duì)于二分類變量的計(jì)數(shù)資料，以比值比（OR）及95%CI作為效應(yīng)量來評(píng)價(jià)rs2279744位點(diǎn)單核苷酸多態(tài)性與乳腺癌發(fā)生的關(guān)系，并繪制Egger漏斗圖檢測(cè)發(fā)表偏倚,最后進(jìn)行敏感性分析。檢驗(yàn)水準(zhǔn)α=0.05。

2 結(jié) 果

2.1 文獻(xiàn)檢索與篩選結(jié)果

通過上述數(shù)據(jù)庫，共檢索到359篇研究，其中中文75篇，英文284篇。剔除重復(fù)發(fā)表的研究97篇，排除不相關(guān)研究42篇，綜述、摘要、會(huì)議文獻(xiàn)及摘要、系統(tǒng)評(píng)價(jià)類研究65篇，動(dòng)物試驗(yàn)23篇，排除非指定位點(diǎn)研究3 0篇，非指定基因研究33篇，非多態(tài)性研究35篇，單體型研究4篇，暫時(shí)獲得研究30篇。進(jìn)一步閱讀文獻(xiàn)內(nèi)容，排除數(shù)據(jù)不全類研究2篇，最終納入Meta分析的研究共計(jì)28篇。文獻(xiàn)檢索流程詳見圖1。

圖1 文獻(xiàn)檢索流程Figure 1 Literature screening process

2.2 納入文獻(xiàn)的一般情況

根據(jù)以上納入、排除標(biāo)準(zhǔn)和質(zhì)量評(píng)價(jià)結(jié)果，有28篇文獻(xiàn)[9-36]納入Meta分析，其中2項(xiàng)研究HWE非平衡（P＜0.05），另外26項(xiàng)研究中均為HWE平衡（P＞0.05），共納入11 804例經(jīng)確診的乳腺癌患者以及15 209例對(duì)照。

表1 納入文獻(xiàn)的一般情況Table 1 The general information of the included studies

2.3 Meta分析結(jié)果

2.3.1 突變型與野生型（TG/GGvs.TT） Meta分析存在異質(zhì)性（I2=32.8%，P＜0.05），應(yīng)配合隨機(jī)效應(yīng)模型進(jìn)行分析。Meta分析結(jié)果顯示，TG/GG和TT基因型在病例組與對(duì)照組中的差異有 統(tǒng) 計(jì) 學(xué) 意 義（OR=1.15，95%CI=1.06～1.24，P＜0.001）（圖2）；另外根據(jù)人群分為4個(gè)亞組，亞洲人群差異有統(tǒng)計(jì)學(xué)意義（隨機(jī)效應(yīng)模型：OR=1.34，95%CI=1.15～1.57，P＜0.001； 固定 效 應(yīng) 模 型：OR=1.34，95%CI=1.20～1.50，P＜0.001）（圖3），敏感性分析圖顯示排除任意一項(xiàng)研究后，結(jié)果仍具有統(tǒng)計(jì)學(xué)差異，波動(dòng)范圍在1.20～1.50，說明結(jié)論的可靠性（圖4）。發(fā)表偏倚評(píng)估，如圖5顯示，Egger漏斗圖對(duì)稱，無明顯偏倚存在（Egger檢驗(yàn)，P=0.971）。

圖2 總?cè)巳和蛔冃团c野生型比較森林圖Figure 2 Forest plot of comparison between mutant genotype and wild genotype in overall population

圖3 亞洲人群突變型與野生型比較森林圖（固定效應(yīng)模型）Figure 3 Forest plot of comparison between mutant genotype and wild genotype in Asia’s population (Fixed effect model)

圖4 突變型與野生型亞洲人群敏感性分析Figure 4 Sensitivity analysis for mutant genotype and wild genotype in Asia’s population

2.3.2 等位基因（Gvs.T） Meta分析存在異質(zhì)性（I2=46.9%，P＜0.05），應(yīng)配合隨機(jī)效應(yīng)模型進(jìn)行分析。Meta分析結(jié)果表明，G和T等位基因病例組與對(duì)照組中的比較，差異有統(tǒng)計(jì)學(xué)意義（OR=1.12，95%=1.05～1.18，P＜0.001）（圖6）；根據(jù)人群分為4個(gè)亞組，亞洲人群差異有統(tǒng)計(jì)學(xué)意義（隨機(jī)效應(yīng)模 型：OR=1.21，95%CI=1.09～1.35，P=0.001）（圖7），敏感性分析圖顯示排除任意一項(xiàng)研究后，結(jié)果仍具有統(tǒng)計(jì)學(xué)差異，波動(dòng)范圍在1.06～1.39，說明結(jié)論的可靠性（圖8）。發(fā)表偏倚評(píng)估顯示，Egger漏斗圖對(duì)稱，無明顯偏倚存在（Egger，P=0.950）（圖9）。

圖5 亞洲人群發(fā)表偏倚評(píng)價(jià)（Egger檢驗(yàn)，P=0.971）Figure 5 Publication bias assessment for mutant genotype and wild genotype in Asia’s population (Egger’s test,P=0.971)

圖6 總?cè)巳旱任换虮容^森林圖Figure 6 Forest plot of comparison between two alleles in overall population

圖7 亞洲人群等位基因比較森林圖（隨機(jī)效應(yīng)模型）Figure 7 Forest plot of comparison between two alleles in Asia’s population (Random effects model)

圖8 等位基因亞洲人群敏感性分析Figure 8 Sensitivity analysis for alleles in Asia’s population

圖9 等位基因亞洲人群發(fā)表偏倚評(píng)價(jià)（Egger，P=0.950）Figure 9 Publication bias assessment for alleles in Asia’s population (Egger’s test, P=0.950)

3 討 論

單核苷酸多態(tài)性是導(dǎo)致基因多樣性的常見來源，學(xué)術(shù)界普遍認(rèn)同其在個(gè)體腫瘤的發(fā)生或演變進(jìn)程中有著不可忽略的作用[37]。MDM2作為一種熱門基因，針對(duì)MDM2基因多態(tài)性與乳腺癌的關(guān)系，目前研究較多的位點(diǎn)包括rs2279744[38-39]，rs3730485[40-41]，rs117039649[11,42]，rs1196333[43]。rs2279744位點(diǎn)是位于MDM2基因啟動(dòng)子區(qū)內(nèi)的第309位（T＞G）突變，其全球最小等位基因頻率G=36.66%，該位點(diǎn)突變與乳腺癌的關(guān)系近年來始終是研究的熱門話題，更深層的研究[44]認(rèn)為該位點(diǎn)突變能夠使得MDM2轉(zhuǎn)錄增強(qiáng)表達(dá)增加，研究表明其多態(tài)性與其他腫瘤，諸如膀胱癌[45]、口腔癌[46]、子宮內(nèi)膜癌[47]、結(jié)直腸癌[48]、肺癌[49]等也可能存在某種聯(lián)系。有關(guān)rs2279744位點(diǎn)單核苷酸多態(tài)性與乳腺癌的關(guān)系尚存在諸多爭(zhēng)議，Yadav等[12]及Krekac等[23]認(rèn)為rs2279744位點(diǎn)單核苷酸多態(tài)性與乳腺癌無直接關(guān)聯(lián)，Isakova等[50]及Sun等[21]認(rèn)為MDM2基因rs2279744單核苷酸多態(tài)性能顯著增加乳腺癌的發(fā)病風(fēng)險(xiǎn)。因?yàn)榇嬖谥T多觀點(diǎn)上的爭(zhēng)議，故有必要通過資料的收集和Meta分析整合來進(jìn)一步探討該基因位點(diǎn)多態(tài)性與乳腺癌的風(fēng)險(xiǎn)關(guān)聯(lián)性。

本次研究通過檢索國(guó)內(nèi)外知名數(shù)據(jù)庫，篩選出28篇MDM2基因rs2279744單核苷酸多態(tài)性與乳腺癌相關(guān)的病例對(duì)照研究，通過Meta分析，比較病例組與對(duì)照組的基因型比例，突變型與野生型（TG/GGvs.TT）有明顯差異，等位基因模型下的病例組與對(duì)照組G/T等位基因（Gvs.T）有明顯差異。但是，經(jīng)過亞組分析發(fā)現(xiàn)，只有在亞洲人群中該位點(diǎn)的突變與乳腺癌發(fā)病相關(guān)。隨后，驗(yàn)證Meta分析結(jié)果的穩(wěn)定性，結(jié)果穩(wěn)定可靠；從漏斗圖的圖示結(jié)果來看，基本對(duì)稱，提示無發(fā)表偏倚或發(fā)表偏倚不明顯。因此認(rèn)為，MDM2基因rs2279744位點(diǎn)的突變與亞洲人乳腺癌的發(fā)生顯著相關(guān)，其極有可能成為亞洲人乳腺癌高?；颊吆Y查的新突變位點(diǎn)，甚至成為乳腺癌治療的新的基因靶點(diǎn)，亟待學(xué)者對(duì)亞洲人群該位點(diǎn)突變的特殊性進(jìn)行下一步研究。

綜上所述，本研究通過Meta分析對(duì)rs2279744位點(diǎn)多態(tài)性與乳腺癌的發(fā)病風(fēng)險(xiǎn)的關(guān)聯(lián)性做出了評(píng)價(jià)，就兩者關(guān)聯(lián)性得出了肯定的結(jié)論。當(dāng)然本研究也存在一些缺陷和不足，例如檢索的數(shù)據(jù)庫數(shù)量不夠多，納入研究均為中文和英文文獻(xiàn)，尚缺乏其他語言類研究，難免造成一定程度的偏倚風(fēng)險(xiǎn)。但是，筆者認(rèn)為，此次大樣本量的綜合研究結(jié)果具有一定的臨床意義，對(duì)于那些存在乳腺癌發(fā)病風(fēng)險(xiǎn)的個(gè)體的篩查，帶來幫助，例如可以作為一項(xiàng)風(fēng)險(xiǎn)評(píng)估項(xiàng)目，篩查出高危患者，對(duì)于那些進(jìn)行MDM2基因rs2279744位點(diǎn)與乳腺癌關(guān)聯(lián)的基礎(chǔ)研究者，也可作為一定的參考。

[1]Dubey AK, Gupta U, Jain S. Breast cancer statistics and prediction methodology: a systematic review and analysis[J]. Asian Pac J Cancer Prev, 2015, 16(10):4237–4245.

[2]Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012[J].CA Cancer J Clin, 2015, 65(2):87–108. doi: 10.3322/caac.21262.

[3]Chen W, Zheng R, Baade PD, et al. Cancer statistics in China,2015[J]. CA Cancer J Clin, 2016, 66(2):115–132. doi: 10.3322/caac.21338.

[4]Sankaranarayanan R. Cancer survival in Africa, Asia, the Caribbean and Central America. Introduction[J]. IARC Sci Publ, 2011,(162):1–5.

[5]姜力豪. 鼠雙微染色體2基因?qū)[狀細(xì)胞癌預(yù)后評(píng)估的研究進(jìn)展[J]. 重慶醫(yī)學(xué), 2013, 42(8):952–954. doi:10.3969/j.issn.1671–8348.2013.08.048.Jiang LH. Research progress of mouse double minute 2 homolog gene in prognostic evaluation of squamous-cell carcinoma[J].Chongqing Medicine, 2013, 42(8):952–954. doi:10.3969/j.issn.1671–8348.2013.08.048.

[6]Oliner JD, Kinzler KW, Meltzer PS, et al. Ampli fi cation of a gene encoding a p53-associated protein in human sarcomas[J]. Nature,1992, 358(6381):80–83.

[7]Mendoza M, Mandani G, Momand J. The MDM2 gene family[J].Biomol Concepts, 2014, 5(1):9–19. doi: 10.1515/bmc-2013–0027.

[8]Zhao Y, Yu H, Hu W. The regulation of MDM2 oncogene and its impact on human cancers[J]. Acta Biochim Biophys Sin (Shanghai),2014, 46(3):180–189. doi: 10.1093/abbs/gmt147.

[9]Copson ER, White H E, Blaydes J P, et al. In fl uence of the MDM2 single nucleotide polymorphism SNP309 on tumour development in BRCA1 mutation carriers[J]. BMC Cancer, 2006,6:80.

[10]Piotrowski P, Lianeri M, Rubis B, et al. Murine double minute clone 2,309T/G and 285G/C promoter single nucleotide polymorphism as a risk factor for breast cancer: a Polish experience[J]. Int J Biol Markers, 2012, 27(2):e105–110. doi: 10.5301/JBM.2012.9140.

[11]Gansmo LB, Knappskog S, Romundstad P, et al. Influence of MDM2 SNP309 and SNP285 status on the risk of cancer in the breast, prostate, lung and colon[J]. Int J Cancer, 2015, 137(1):96–103. doi: 10.1002/ijc.29358.

[12]Yadav P, Masroor M, Tanwer K, et al. Clinical significance of TP53 (R72P) and MDM2 (T309G) polymorphisms in breast cancer patients[J]. Clin Transl Oncol, 2016, 18(7):728–734. doi: 10.1007/s12094–015–1425–5.

[13]Samuel N, Id Said B, Guha T, et al. Assessment of TP53 Polymorphisms and MDM2 SNP309 in Premenopausal Breast Cancer Risk[J]. Hum Mutat, 2017, 38(3):265–268. doi: 10.1002/humu.23154.

[14]吳燦, 徐曄, 歐陽濤, 等. MDM2啟動(dòng)子區(qū)309位點(diǎn)基因多態(tài)性與乳腺癌風(fēng)險(xiǎn)的關(guān)系[J]. 中國(guó)腫瘤臨床, 2010, 37(3):131–133.doi:10.3969/j.issn.1000–8179.2010.03.003.Wu C, Xu Y, Ouyang T, et al. Association between MDM2 SNP309 Polymorphism and Breast Cancer Risk in Chinese Women[J].Chinese Journal of Clinical Oncology, 2010, 37(3):131–133.doi:10.3969/j.issn.1000–8179.2010.03.003.

[15]宋傳貴, 傅芳萌, 吳雪英, 等. MDM2基因SNP309可能與早發(fā)性乳腺癌易感性無關(guān):福建病例-對(duì)照研究[J]. 中國(guó)癌癥雜志, 2011,21(4):262–265. doi:10.3969/j.issn.1007–3969.2011.04.005.Song CG, Fu FM, Wu XY, et al. SNP309 in MDM2 gene may be not associated with susceptibility of early-onset breast cancer: report from Fujian province[J]. China Oncology, 2011, 21(4):262–265.doi:10.3969/j.issn.1007–3969.2011.04.005.

[16]王梅麗, 徐云霞, 錢健, 等. 鼠雙微體-2基因多態(tài)及P53基因多態(tài)與乳腺癌易感性的關(guān)聯(lián)研究[J]. 中華預(yù)防醫(yī)學(xué)雜志, 2013,47(2):124–128. doi:10.3760/cma.j.issn.0253–9624.2013.02.007.Wang ML, Xu YX, Qian J, et al. Association of murine double minute 2 and P53 polymorphisms with breast cancer susceptibility[J]. Chinese Journal of Preventive Medicine, 2013,47(2):124–128. doi:10.3760/cma.j.issn.0253–9624.2013.02.007.

[17]Alshatwi AA, Hasan TN, Shafi G, et al. A single-nucleotide polymorphism in the TP53 and MDM-2 gene modi fi es breast cancer risk in an ethnic Arab population[J]. Fundam Clin Pharmacol, 2012,26(3):438–443. doi: 10.1111/j.1472–8206.2011.00939.x.

[18]Koh WP, Van Den Berg D, Jin A, et al. Combined effects of MDM2 SNP309 and TP53 R72P polymorphisms, and soy isoflavones on breast cancer risk among Chinese women in Singapore[J]. Breast Cancer Res Treat, 2011, 130(3):1011–1019. doi: 10.1007/s10549–011–1680–2.

[19]Leu JD, Wang CY, Tsai HY, et al. Involvement of p53 R72P polymorphism in the association of MDM2-SNP309 with breast cancer[J]. Oncol Rep, 2011, 25(6):1755–1763. doi: 10.3892/or.2011.1254.

[20]L?ng A, Palmeb?ck Wegman P, Wingren S. The significance of MDM2 SNP309 and p53 Arg72Pro in young women with breast cancer[J]. Oncol Rep, 2009, 22(3):575–579.

[21]Sun YF, Leu JD, Chen SM, et al. Results based on 124 cases of breast cancer and 97 controls from Taiwan suggest that the single nucleotide polymorphism (SNP309) in the MDM2 gene promoter is associated with earlier onset and increased risk of breast cancer[J].BMC Cancer, 2009, 9:13. doi: 10.1186/1471–2407–9–13.

[22]Paulin FE, O'Neill M, McGregor G, et al. MDM2 SNP309 is associated with high grade node positive breast tumours and is in linkage disequilibrium with a novel MDM2 intron 1 polymorphism[J]. BMC Cancer, 2008, 8:281. doi: 10.1186/1471–2407–8–281.

[23]Krekac D, Brozkova K, Knoflickova D, et al. MDM2SNP309 does not associate with elevated MDM2 protein expression or breast cancer risk[J]. Oncology, 2008, 74(1/2):84–87. doi:10.1159/000139135.

[24]Lum SS, Chua HW, Li H, et al. MDM2 SNP309 G allele increases risk but the T allele is associated with earlier onset age of sporadic breast cancers in the Chinese population[J]. Carcinogenesis, 2008,29(4):754–761. doi: 10.1093/carcin/bgn024.

[25]Yarden RI, Friedman E, Metsuyanim S, et al. MDM2 SNP309 accelerates breast and ovarian carcinogenesis in BRCA1 and BRCA2 carriers of Jewish-Ashkenazi descent[J]. Breast Cancer Res Treat, 2008, 111(3):497–504.

[26]Singh V, Rastogi N, Mathur N, et al. Association of polymorphism in MDM-2 and p53 genes with breast cancer risk in Indian women[J]. Ann Epidemiol, 2008, 18(1):48–57.

[27]Cox DG, Deer D, Guo Q, et al. The p53 Arg72Pro and MDM2-309 polymorphisms and risk of breast cancer in the nurses' health studies[J]. Cancer Causes Control, 2007, 18(6):621–625.

[28]Wasielewski M, Nagel J H, Brekelmans C, et al. MDM2 SNP309 accelerates familial breast carcinogenesis independently of estrogen signaling[J]. Breast Cancer Res Treat, 2007, 104(2):153–157.

[29]Petenkaya A, Bozkurt B, Akilli-Ozturk O, et al. Lack of association between the MDM2-SNP309 polymorphism and breast cancer risk[J]. Anticancer Res, 2006, 26(6C):4975–4977.

[30]Boersma BJ, Howe TM, Goodman JE, et al. Association of breast cancer outcome with status of p53 and MDM2 SNP309[J]. J Natl Cancer Inst, 2006, 98(13):911–919.

[31]Wilkening S, Bermejo J L, Burwinkel B, et al. The single nucleotide polymorphism IVS1+309 in mouse double minute 2 does not affect risk of familial breast cancer[J]. Cancer Res, 2006, 66(2):646–648.

[32]Campbell IG, Eccles DM, Choong DY. No association of the MDM2 SNP309 polymorphism with risk of breast or ovarian cancer[J]. Cancer Lett, 2006, 240(2):195–197.

[33]Ma H, Hu Z, Zhai X, et al. Polymorphisms in the MDM2 promoter and risk of breast cancer: a case-control analysis in a Chinese population[J]. Cancer Letters, 2006, 240(2):261–267.

[34]Millikan RC, Heard K, Winkel S, et al. No association between the MDM2 -309 T/G promoter polymorphism and breast cancer in African-Americans or Whites[J]. Cancer Epidemiol Biomarkers Prev, 2006, 15(1):175–177.

[35]Akisik E, Yazici H, Dalay N. ARLTS1, MDM2 and RAD51 gene variations are associated with familial breast cancer[J]. Mol Biol Rep, 2011, 38(1):343–348. doi: 10.1007/s11033–010–0113–3.

[36]Macedo GS, Vieira IA, Vianna FSL, et al. p53 signaling pathway polymorphisms, cancer risk and tumor phenotype in TP53 R337H mutation carriers[J]. Fam Cancer, 2017, doi: 10.1007/s10689–017–0028–4. [Epub ahead of print]

[37]Wilkening S, Bermejo JL, Hemminki K. MDM2 SNP309 and cancer risk: a combined analysis[J]. Carcinogenesis, 2007,28(11):2262–2267.

[38]Zhao E, Cui D, Yuan L, et al. MDM2 SNP309 polymorphism and breast cancer risk: a meta-analysis[J]. Mol Biol Rep, 2012,39(4):3471–3477. doi: 10.1007/s11033–011–1119–1.

[39]Gao J, Kang A, Lin S, et al. Association between MDM2 rs 2279744 polymorphism and breast cancer susceptibility: a metaanalysis based on 9,788 cases and 11,195 controls[J]. Ther Clin Risk Manag, 2014, 10:269–277. doi: 10.2147/TCRM.S60680.

[40]Gallegos-Arreola MP, Márquez-Rosales MG, Sánchez-Corona J, et al. Association of the Del1518 Promoter (rs3730485) Polymorphism in the MDM2 Gene with Breast Cancer in a Mexican Population[J].Ann Clin Lab Sci, 2017, 47(3):291–297.

[41]Gansmo LB, Vatten L, Romundstad P, et al. Associations between the MDM2 promoter P1 polymorphism del1518(rs3730485) and incidence of cancer of the breast, lung, colon and prostate[J]. Oncotarget, 2016, 7(19):28637–28646. doi: 10.18632/oncotarget.8705.

[42]Knappskog S, Lonning P E. MDM2 promoter SNP285 and SNP309; phylogeny and impact on cancer risk[J]. Oncotarget, 2011,2(3):251–258.

[43]Knappskog S, Gansmo L B, Romundstad P, et al. MDM2 promoter SNP344T＞A (rs1196333) status does not affect cancer risk[J]. PLoS One, 2012, 7(4):e36263. doi: 10.1371/journal.pone.0036263.

[44]Bond GL, Hu W, Bond EE, et al. A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans[J]. Cell, 2004,119(5):591–602.

[45]Xie L, Sun Y, Chen T, et al. Association between MDM2 SNP309 T＞G polymorphism and the risk of bladder cancer: new data in a Chinese population and an updated meta-analysis[J]. Onco Targets Ther, 2015, 8:3679–3690. doi: 10.2147/OTT.S95353.

[46]Yang XI, Zhu Y, Ye D, et al. Association of MDM2 promoter T309G polymorphism with oral cancer risk: A meta-analysis of 3,536 subjects[J]. Mol Clin Oncol, 2016, 5(1):175–180.

[47]Zajac A, Smolarz B, Stachowiak G, et al. TP53 and MDM2 polymorphisms and the risk of endometrial cancer in postmenopausal women[J]. Med Oncol, 2014, 31(11):286. doi:10.1007/s12032–014–0286-z.

[48]Wang W, Du M, Gu D, et al. MDM2 SNP309 polymorphism is associated with colorectal cancer risk[J]. Sci Rep, 2014, 4:4851.doi: 10.1038/srep04851.

[49]Kong Q, Li P, Tian Q, et al. Role of MDM2 T309G polymorphism in susceptibility and prognosis of nonsmall cell lung cancer: a metaanalysis[J]. Genet Test Mol Biomarkers, 2014, 18(5):357–365. doi:10.1089/gtmb.2013.0506.

[50]Isakova JT, Talaibekova ET, Makieva KB, et al. Association between XRCC1 ARG399GLN, TP53 ARG72PRO and MDM2 T309G polymorphisms and the risk of breast cancer in women of the Kyrgyz population[J]. Rossiiskii Onkologicheskii Zhurnal,2016, 21(3):131–135.