林 瑩，閆 艷，吳 崢，葛瀟瀟，林鳳娟，李 進(jìn),3

1.復(fù)旦大學(xué)附屬腫瘤醫(yī)院腫瘤內(nèi)科，復(fù)旦大學(xué)上海醫(yī)學(xué)院腫瘤學(xué)系，上海 200032；2.上海交通大學(xué)醫(yī)學(xué)院附屬瑞金醫(yī)院腫瘤科，上海 200025；3.同濟(jì)大學(xué)附屬天佑醫(yī)院腫瘤科，上海 200311

胃癌組織原鈣黏蛋白10 mRNA表達(dá)水平與預(yù)后的相關(guān)性

林 瑩1，閆 艷1，吳 崢2，葛瀟瀟1，林鳳娟1，李 進(jìn)1,3

1.復(fù)旦大學(xué)附屬腫瘤醫(yī)院腫瘤內(nèi)科，復(fù)旦大學(xué)上海醫(yī)學(xué)院腫瘤學(xué)系，上海 200032；2.上海交通大學(xué)醫(yī)學(xué)院附屬瑞金醫(yī)院腫瘤科，上海 200025；3.同濟(jì)大學(xué)附屬天佑醫(yī)院腫瘤科，上海 200311

背景與目的：編碼原鈣黏蛋白10(protocadherin-10，PCDH10)的PCDH10基因啟動(dòng)子甲基化與胃癌患者不良預(yù)后相關(guān)。但PCDH10表達(dá)水平與胃癌預(yù)后的關(guān)系不明確。該研究旨在分析PCDH10表達(dá)水平與胃癌預(yù)后及臨床病理因素間的關(guān)系，尋找預(yù)測(cè)胃癌患者復(fù)發(fā)及死亡風(fēng)險(xiǎn)的指標(biāo)。方法：采用實(shí)時(shí)熒光定量聚合酶鏈反應(yīng)(real-time fluorescent quantitative polymerase chain reaction，RTFQ-PCR)方法檢測(cè)115對(duì)胃癌組織與相應(yīng)癌旁組織PCDH10 mRNA的表達(dá)水平，分析PCDH10 mRNA的表達(dá)水平與預(yù)后及臨床病理因素的關(guān)系。采用Logistic回歸分析建立預(yù)測(cè)患者5年內(nèi)復(fù)發(fā)或死亡風(fēng)險(xiǎn)的模型。結(jié)果：PCDH10 mRNA低表達(dá)組與非低表達(dá)組相比，無(wú)進(jìn)展生存時(shí)間(progression-free survival，PFS)與總生存時(shí)間(overall survival，OS)顯著延長(zhǎng)(P值分別為0.046與0.033)，淋巴結(jié)轉(zhuǎn)移較少(P=0.001)，TNM分期較早(P=0.001)。Cox單因素分析發(fā)現(xiàn)，Lauren分型、T分期、N分期、M分期及PCDH10 mRNA表達(dá)水平與PFS及OS顯著相關(guān)。包含PCDH10作為參數(shù)的Logistic回歸模型對(duì)胃癌患者術(shù)后5年內(nèi)復(fù)發(fā)或死亡風(fēng)險(xiǎn)的預(yù)測(cè)效率與僅包含傳統(tǒng)臨床病理學(xué)參數(shù)的Logistic回歸模型的預(yù)測(cè)效率相當(dāng)。結(jié)論：PCDH10低表達(dá)胃癌患者淋巴結(jié)轉(zhuǎn)移較少，TNM分期較早，預(yù)后較好，可以作為預(yù)測(cè)胃癌患者預(yù)后的輔助指標(biāo)?；赑CDH10表達(dá)水平的Logistic回歸模型可以在淋巴結(jié)轉(zhuǎn)移情況不明時(shí)起到輔助判斷患者預(yù)后的作用。

胃癌；原鈣黏蛋白10； 表達(dá)； 預(yù)后

胃癌是全球最常見的腫瘤之一。在中國(guó)，胃癌的發(fā)病率和死亡率在腫瘤性疾病中分別居于第2位和第3位［1］。盡管近年來(lái)胃癌的發(fā)病率和死亡率在逐漸下降，但胃癌的預(yù)后并沒有顯著改善［2］。尋找能指示胃癌預(yù)后的生物學(xué)標(biāo)志物不僅有助于臨床醫(yī)生判斷預(yù)后并制定個(gè)體化治療方案，也有助于明確胃癌發(fā)生、發(fā)展的機(jī)制，對(duì)制定胃癌的治療策略有重要意義。

近年來(lái)的研究發(fā)現(xiàn)，編碼原鈣黏蛋白10(protocadherin-10，PCDH10)的PCDH10基因啟動(dòng)子甲基化可能參與胃癌發(fā)生、發(fā)展的過(guò)程［3］。包括胃癌在內(nèi)的多種腫瘤組織及腫瘤細(xì)胞系存在PCDH10基因甲基化現(xiàn)象，PCDH10表達(dá)量降低與腫瘤組織及腫瘤細(xì)胞中PCDH10基因甲基化水平相關(guān)［4-20］。在胃癌及其他數(shù)種腫瘤中，PCDH10基因的甲基化水平與臨床不良預(yù)后相關(guān)［4,7-9,13,20］，但是PCDH10的表達(dá)水平與胃癌預(yù)后及臨床病理因素間的關(guān)系仍不明確。

為了進(jìn)一步研究PCDH10與胃癌發(fā)生、發(fā)展的關(guān)系，本研究檢測(cè)了115例胃癌及癌旁組織中PCDH10 mRNA表達(dá)水平，分析PCDH10的表達(dá)水平與預(yù)后及臨床病理因素的關(guān)系，建立基于PCDH10表達(dá)水平的預(yù)測(cè)胃癌患者復(fù)發(fā)及死亡的Logistic回歸模型。

1 資料和方法

1.1 臨床資料

本研究所使用的115例胃癌與相應(yīng)癌旁組織標(biāo)本均來(lái)自2008—2009年在復(fù)旦大學(xué)附屬腫瘤醫(yī)院行胃癌切除術(shù)的患者的手術(shù)切除標(biāo)本，由復(fù)旦大學(xué)附屬腫瘤醫(yī)院組織庫(kù)保存。所有患者術(shù)前均知情并簽署復(fù)旦大學(xué)附屬腫瘤醫(yī)院組織庫(kù)樣本采集知情同意書。樣本選取標(biāo)準(zhǔn)如下：① 病理診斷為胃腺癌；② 術(shù)前未接受放化療；③ 無(wú)其他惡性腫瘤病史；④ 臨床資料及5年隨訪資料完整。所有標(biāo)本病理診斷明確，并統(tǒng)一根據(jù)美國(guó)癌癥聯(lián)合會(huì)(American Joint Committe on Cancer，AJCC)第七版TNM分期標(biāo)準(zhǔn)進(jìn)行分期。術(shù)后輔助治療及一線、二線治療均以患者就診當(dāng)時(shí)最新的NCCN指南為統(tǒng)一的治療原則進(jìn)行。

1.2 RNA提取及實(shí)時(shí)熒光定量聚合酶鏈反應(yīng)(real-time fluorescent quantitative polymeras chain reaction，RTFQ-PCR)檢測(cè)

采用TRIzol法提取組織中的總RNA，反轉(zhuǎn)錄并進(jìn)行RTFQ-PCR。RTFQ-PC所用的PCDH10的引物為：上游引物5’-ACTGCTATCAGGTATGCCTG-3’；下游引物5’-GTCTGTCAACTAGATAGCTG-3’。以18s核糖體RNA(18s rRNA)為RTFQPCR的內(nèi)參，所用引物為：上游引物5’-CGGCTACCACATCCAAGGAAG-3’；下游引物 5’-GCTGGAATTACCGCGGCTGCT-3’。PCDH10 mRNA相對(duì)于18s rRNA的表達(dá)量的計(jì)算方法為2-ΔCt(ΔCt=癌或癌旁組織中PCDH10的Ct值-同一樣本中18s rRNA的Ct值)。PCDH10 mRNA在胃癌組織與癌旁組織中的相對(duì)表達(dá)量的計(jì)算方法為：2-ΔΔCt(ΔΔCt=ΔCt癌組織-ΔCt相應(yīng)癌旁組織)。根據(jù)胃癌組織相對(duì)癌旁組織的PCDH10表達(dá)水平將樣本分成3組，小于等于0.5為低表達(dá)組，大于等于2為高表達(dá)組，介于兩者之間為無(wú)顯著差異組。

1.3 隨訪情況

本研究隨訪終點(diǎn)為患者發(fā)生死亡事件或隨訪時(shí)間已滿5年。無(wú)進(jìn)展生存期(progression-free survival，PFS)定義為從接受手術(shù)開始到患者出現(xiàn)腫瘤進(jìn)展或死亡的時(shí)間?？偵鏁r(shí)間(overall survival，OS)定義為患者自接受手術(shù)之日起至死亡之日或隨訪結(jié)束之日的時(shí)間。

1.4 統(tǒng)計(jì)學(xué)處理

采用SPSS 19.0軟件進(jìn)行統(tǒng)計(jì)學(xué)分析。采用Kaplan-Meier方法及Log-rank檢驗(yàn)評(píng)估PCDH10 mRNA表達(dá)水平與PFS、OS的關(guān)系。采用配對(duì)t檢驗(yàn)評(píng)估胃癌組織與癌旁組織PCDH10 mRNA表達(dá)差異，采用χ2檢驗(yàn)評(píng)估PCDH10相對(duì)表達(dá)水平與臨床病理因素的關(guān)系。雙側(cè)檢驗(yàn)P<0.05為差異有統(tǒng)計(jì)學(xué)意義。用二元Logistic回歸分析建立Logistic回歸模型。采用Cox回歸分析單因素與PFS、OS的關(guān)系，P<0.05為差異有統(tǒng)計(jì)學(xué)意義。

2 結(jié)果

2.1 胃癌及癌旁組織PCDH10 mRNA表達(dá)水平的差異

在115例樣本中，41例樣本(35.7%)存在PCDH10 mRNA表達(dá)水平的下調(diào)，39例樣本(33.9%)存在PCDH10 mRNA表達(dá)水平的上調(diào)，其余35例樣本(30.4%)未檢測(cè)到PCDH10 mRNA水平明顯變化。胃癌組織中的PCDH10 mRNA平均表達(dá)水平顯著高于癌旁組織(P=0.039 7，圖1)。

2.2 PCDH10 mRNA相對(duì)表達(dá)水平與胃癌預(yù)后的關(guān)系

根據(jù)PCDH10 mRNA相對(duì)表達(dá)水平將樣本分為高表達(dá)組、等表達(dá)組和低表達(dá)組，進(jìn)行Kaplan-Meier生存分析，成對(duì)比較結(jié)果顯示，PCDH10 mRNA高表達(dá)組與PCDH10 mRNA等表達(dá)組的PFS和OS差異無(wú)統(tǒng)計(jì)學(xué)意義(P=0.718和P=0.466)，故將改兩組合并為非低表達(dá)組。再次分析結(jié)果表明，PCDH10 mRNA低表達(dá)組PFS及OS均較非低表達(dá)組顯著延長(zhǎng)(圖2，P=0.046和P=0.033)。

圖 1 胃癌與癌旁組織中PCDH10 mRNA表達(dá)水平的差異Fig. 1 PCDH10 mRNA expression in gastric cancer tissues and adjacent normal gastric tissues

圖 2 PCDH10低表達(dá)組與非低表達(dá)組患者的無(wú)進(jìn)展生存曲線及總生存曲線Fig. 2 Kaplan-Meier analysis of PFS and OS in gastric cancer patients with different expressions of PCDH10

2.3 PCDH10 mRNA相對(duì)表達(dá)水平與胃癌患者臨床病理特征的關(guān)系

PCDH10 mRNA相對(duì)表達(dá)水平與胃癌患者臨床病理特征的關(guān)系見表1。PCDH10表達(dá)下調(diào)與TNM分期較早及淋巴結(jié)轉(zhuǎn)移較少顯著相關(guān)(P=0.001和P=0.001)，且PCDH10表達(dá)下調(diào)在女性患者中比在男性患者中更常見(P=0.040)。PCDH10表達(dá)與年齡、Lauren分型、T分期、神經(jīng)浸潤(rùn)及脈管浸潤(rùn)等臨床病理特征之間無(wú)明顯相關(guān)關(guān)系。

2.4 臨床病理特征及PCDH10 mRNA表達(dá)水平與胃癌患者預(yù)后的Cox單因素分析

Cox單因素分析發(fā)現(xiàn)Lauren分型、T分期、N分期、M分期及PCDH10 mRNA表達(dá)水平與胃癌患者的PFS及OS均顯著相關(guān)，而年齡和性別與胃癌患者的預(yù)后無(wú)顯著相關(guān)性(表2、3)。

2.5 Logistic回歸模型

根據(jù)Cox單因素分析結(jié)果，將與胃癌患者PFS及OS有顯著相關(guān)性的Lauren分型、T分期、N分期、M分期及PCDH10 mRNA相對(duì)表達(dá)水平納入Logistic回歸模型。基于傳統(tǒng)臨床病理學(xué)參數(shù)的預(yù)測(cè)胃癌5年內(nèi)復(fù)發(fā)或死亡風(fēng)險(xiǎn)的Logistic回歸模型納入了Lauren分型、T分期、N分期和M分期作為參數(shù)。基于PCDH10表達(dá)水平的預(yù)測(cè)胃癌5年內(nèi)復(fù)發(fā)或死亡風(fēng)險(xiǎn)的Logistic回歸模型納入了Lauren分型、T分期、M分期及PCDH10 mRNA表達(dá)水平作為參數(shù)，但未包括N分期為參數(shù)?；趥鹘y(tǒng)臨床病理學(xué)參數(shù)預(yù)測(cè)胃癌5年內(nèi)復(fù)發(fā)風(fēng)險(xiǎn)模型受試者工作特征(receiver operating characteristic，ROC)曲線的曲線下面積(0.744，95%CI：0.651 ～0.837)與基于PCDH10 mRNA表達(dá)水平預(yù)測(cè)胃癌5年內(nèi)復(fù)發(fā)風(fēng)險(xiǎn)模型的曲線下面積(0.717，95%CI：0.623 ～0.811)差異無(wú)統(tǒng)計(jì)學(xué)意義(P>0.05，圖3)?；趥鹘y(tǒng)臨床病理學(xué)參數(shù)預(yù)測(cè)胃癌5年內(nèi)死亡風(fēng)險(xiǎn)模型ROC曲線的曲線下面積(0.749，95%CI：0.658 ～0.840)與基于PCDH10 mRNA表達(dá)水平預(yù)測(cè)胃癌5年內(nèi)死亡風(fēng)險(xiǎn)模型的曲線下面積(0.729，95%CI：0.637 ～0.820)差異無(wú)統(tǒng)計(jì)學(xué)意義(P>0.05，圖3)。提示兩類模型效率相當(dāng)。由于基于PCDH10表達(dá)水平的Logistic回歸模型不需要N分期作為參數(shù)，它可以在臨床N分期資料不全的情況下起到替代N分期，輔助判斷患者預(yù)后、指導(dǎo)臨床治療與隨訪的作用。

表 1 PCDH10 mRNA表達(dá)水平與胃癌患者臨床病理特征的關(guān)系Tab. 1 Correlation between the expression of PCDH10 mRNA and clinicopathological features of gastric cancer[n(%)]

表 2 臨床病理特征及PCDH10 mRNA表達(dá)水平與胃癌患者PFS的Cox單因素分析Tab. 2 The correlation between clinicopathological characteristics and expression of PCDH10 mRNA and PFS in gastric cancer patients: univariate Cox’s regression analysis

表 3 臨床病理特征及PCDH10 mRNA表達(dá)水平與胃癌患者OS的Cox單因素分析Tab. 3 The correlation between clinicopathological characteristics and expression of PCDH10 mRNA and OS in gastric cancer patients: univariate Cox’s regression analysis

圖 3 兩類預(yù)測(cè)胃癌5年內(nèi)復(fù)發(fā)或死亡風(fēng)險(xiǎn)模型的ROC曲線Fig. 3 ROC curves of two kinds of prediction models of recurrence or death in 5 years for gastric cancer

3 討論

在胃癌的綜合治療中，傳統(tǒng)的TNM分期對(duì)預(yù)測(cè)患者預(yù)后有一定的輔助作用，但臨床上存在因病理資料不全而影響預(yù)后判斷及治療決策的情況，如術(shù)中淋巴結(jié)清掃不當(dāng)導(dǎo)致對(duì)淋巴結(jié)轉(zhuǎn)移情況的誤判等，因此尋找客觀的生物學(xué)標(biāo)志物輔助臨床判斷與決策是十分重要的。

本研究發(fā)現(xiàn)，PCDH10 mRNA低表達(dá)組胃癌患者TNM分期較早，淋巴結(jié)轉(zhuǎn)移較少，預(yù)后較好，可以作為胃癌患者預(yù)后的指標(biāo)之一?；赑CDH10表達(dá)水平的Logistic回歸模型(包括Lauren分型、T分期、M分期及PCDH10 mRNA表達(dá)水平為參數(shù))對(duì)5年內(nèi)復(fù)發(fā)或死亡的預(yù)測(cè)效率與基于傳統(tǒng)臨床病理學(xué)參數(shù)(包括Lauren分型、T分期、N分期及M分期)的Logistic回歸模型的預(yù)測(cè)效率相當(dāng)。由于基于PCDH10表達(dá)水平的Logistic回歸模型不需要將N分期作為預(yù)測(cè)的參數(shù)之一，在臨床應(yīng)用中，可作為淋巴結(jié)轉(zhuǎn)移情況不明或因各種原因術(shù)中沒有進(jìn)行充分的淋巴結(jié)清掃的胃癌患者判斷預(yù)后、指導(dǎo)治療和隨訪的輔助指標(biāo)。

但本研究發(fā)現(xiàn)，PCDH10低表達(dá)胃癌患者預(yù)后較好的結(jié)論與文獻(xiàn)報(bào)道的PCDH10基因是抑癌基因的結(jié)論不符。原因可能包括：① 各個(gè)研究的樣本量較少，而且目前只有關(guān)于PCDH10基因甲基化水平與胃癌預(yù)后的研究，而PCDH10表達(dá)水平與胃癌預(yù)后的關(guān)系仍不明確；② 關(guān)于PCDH10基因在胃癌細(xì)胞中的功能研究較少，且機(jī)制仍不清楚。Yu等［7］及Li等［19］分別在胃癌細(xì)胞中進(jìn)行了PCDH10的功能研究，兩項(xiàng)研究均發(fā)現(xiàn)，PCDH10過(guò)表達(dá)或再表達(dá)可抑制腫瘤生長(zhǎng)和遷移［7，19］。Yu等［7］研究發(fā)現(xiàn)，PCDH10過(guò)表達(dá)可以誘導(dǎo)凋亡，但是Li等［19］研究發(fā)現(xiàn)，PCDH10對(duì)細(xì)胞凋亡的影響不明顯。兩研究結(jié)果間不一致提示了PCDH10在胃癌發(fā)生、發(fā)展中的作用及其機(jī)制仍不清楚。Zhao等［5］研究發(fā)現(xiàn)，PCDH10在子宮內(nèi)膜癌中是作為Wnt通路的負(fù)調(diào)控因子，在胃癌中是否也通過(guò)同樣的通路起作用仍需進(jìn)一步研究。雖然目前認(rèn)為原鈣黏蛋白基因大多為抑癌基因，但是編碼原鈣黏蛋白7(protocadherin-7，PCDH7)的PCDH7基因在乳腺癌中存在表達(dá)水平升高的現(xiàn)象，可能與乳腺癌的轉(zhuǎn)移有關(guān)［21-22］。提示原鈣黏蛋白家族的每個(gè)基因可能作用不同。關(guān)于PCDH10在胃癌發(fā)生、發(fā)展中的作用及其機(jī)制及其與預(yù)后的關(guān)系還有待進(jìn)一步研究。

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Correlation between mRNA expression of protocadherin-10 and prognosis in gastric cancer

LINYing1, YAN Yan1, WU Zheng2, GE Xiaoxiao1, LIN Fengjuan1, LI Jin1,3
(1. Department of Medical Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; 2. Department of Oncology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; 3. Department of Oncology, Tongji University Tianyou Hospital, Shanghai 200331, China)

LI Jin E-mail: tianyoulijin@163.com

Background and purpose:Promoter methylation of PCDH10, a gene encoding protocadherin 10, has been found to be correlated to poor prognosis in gastric cancer (GC) patients. However, the relationship between the expression of PCDH10 and prognosis in GC remained unknown. This study aimed to explore the relationship between the expression of PCDH10 and clinicopathological features and prognosis of GC, and to identify biomarker for predictions of recurrence and survival of GC.Methods:mRNA expressions of PCDH10 in 115 pairs of GC tissues and adjacent normal tissues were detected by real-time fluorescence quantitative polymerase chain reaction (RTFQ-PCR). The correlation between PCDH10 expression level and clinicopathological features and prognosis of GC was analyzed. Prediction models for 5-year recurrence and 5-year survival were established using logistic regression method.Results:Progression-free survival (PFS) and overall survival (OS) were significantly prolonged in patients with PCDH10 lowexpression compared to patients without PCDH10 low expression (P=0.046 and P=0.033 respectively). PCDH10 low expression significantly correlated with less lymph node metastasis (P=0.001) and earlier TNM staging (P=0.001), and was more common in female than in male (P=0.040). The mRNA expression of PCDH10 did not correlate with age, Lauren classification, T stage, neural invasion or vascular invasion. Univariate Cox analysis showed Lauren classification, T stage, N stage, M stage and PCDH10 expression significantly correlated with PFS and OS. Logistic regression models for the prediction of 5-year recurrence or 5-year survival based on clinicopathological features included Lauren classification, T stage, N stage and M stage as variables. Logistic regression models for the prediction of 5-year recurrence or 5-year survival based on PCDH10 expression included Lauren classification, T stage, M stage and PCDH10 expression level but not N stage as variables. The models based on PCDH10 expression had the same efficiencies as models based on clinical parameters in predicting 5-year recurrence or 5-year survival for GC patients.Conclusion:PCDH10 low expression correlated with better prognosis, less lymph node metastasis and earlier TNM stage in GC patients. Low expression of PCDH10 may be a biomarker of better survival for GC patients. Logistic regression model based on PCDH10 mRNA expression may serve as a prediction model when patients have unknown lymph node metastasis status.

Gastric cancer; Protocadherin-10; Expression; Prognosis

10.19401/j.cnki.1007-3639.2017.01.002

R735.2

A

1007-3639(2017)01-0007-07

2016-07-18

2016-09-01）

國(guó)家科技重大專項(xiàng)基金(2012ZX09303-018-002)。

李 進(jìn) E-mail: tianyoulijin@163.com