CN107653318A - 一组用于预测鼻咽癌转移风险的标志物及其应用 - Google Patents
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Abstract
本发明公开了一组用于预测鼻咽癌转移风险的标志物及其应用。标志物包括ANXA1、CBR3、CLASP1、CXCL10、DCTN1、FNDC3B、LRIG1、FNDC3B、HDLBP、POLR2M、WSB2、WNK1、YBX3。本发明13个基因表达构成的分子标签,可以反映鼻咽癌患者的生物学特异性,可以更准确地预测鼻咽癌患者的转移风险及预后,更好地指导临床用药,对无远处生存的预测效能要优于传统N分期。
Description
技术领域
本发明涉及鼻咽癌的预后标志物,特别涉及一组用于预测鼻咽癌转移风险的标志物及其应用。
背景技术
全球40%的鼻咽癌(NPC)发生在中国,广东省等华南地区最为高发,70%患者就诊时已属中晚期,严重威胁着我国人民的生命健康。近年来,随着现代影像技术的应用和调强放射治疗技术的进步,鼻咽癌的局部控制率明显提高,远处转移成为治疗失败的主要模式。根据文献报道,鼻咽癌患者在初诊根治性治疗后的远处转移率高达30~40%,且转移性鼻咽癌患者对治疗的反应性差,预后不良,其中位生存期约12个月,3年生存率不到10%。
目前,临床上主要是根据解剖学分期(TNM,T是原发灶,N是淋巴结,M是远处转移)来预测鼻咽癌远处转移,并根据分期决定不同的治疗策略。TNM分期最大的问题在于仅仅基于肿瘤的解剖学侵犯范围,而完全没有考虑肿瘤的生物学异质性。同样大小的肿瘤,其内在的生物学特性和转移潜能可能存在很大差异。临床分期相同的患者接受了相同的治疗,预后却可能截然不同。比如淋巴结分期为N3的鼻咽癌患者有35%会发生转移,另外的65%却不会发生转移;而治疗前没有淋巴结转移(N0期)的患者,有10%会在治疗中或治疗后发生转移。显然,仅仅依靠临床分期并不能非常准确地区分患者的转移风险,从而给予针对性的治疗,一部分患者可能接受了过度治疗,另一部分患者的治疗强度却可能不足。为了更准确地预测转移,提高治疗的针对性和有效性,亟需寻找新的反映肿瘤转移潜能的生物学标志物。
甄别具有“转移潜能”的鼻咽癌患者,做到提前预测并给予有效的治疗,可以显著改善这部分患者的预后。
发明内容
本发明的目的在于提供一组可以有效预测NPC转移风险的标志物。
本发明的另一个目的在于该组标志物在制备NPC预后试剂中的应用。
本发明所采取的技术方案是:
一组用于预测鼻咽癌转移风险的标志物,该组标志物包括ANXA1、CBR3、CLASP1、CXCL10、DCTN1、FNDC3B、LRIG1、FNDC3B、HDLBP、POLR2M、WSB2、WNK1、YBX3。
作为上述标志物的进一步改进,用于NPC风险预测的评分公式根据Cox风险比例模型确定。
作为上述标志物的进一步改进,用于NPC风险预测的评分公式为:分值=(0.1846×YBX3表达量)-(0.3007×CBR3表达量)-(0.1383×CXCL10表达量)-(0.3661×CLASP1表达量)+(0.2381×DCTN1表达量)-(0.4004×FNDC3B表达量)+(0.6×WSB2表达量)+(0.1093×LRIG1表达量)-(0.1162×GRM4表达量)+(0.1327×ANXA1表达量)+(0.1485×WNK1表达量)+(0.0714×HDLBP表达量)+(0.1774×POLR2M表达量)。
用于确定标志物相对表达量的内参基因选自ACTB、B2M、PGK1、RPL19、RPLP0。特别的,上述标志物的表达量基于ACTB、B2M、PGK1、RPL19、RPLP0五个内参基因的几何均数进行计算。
通过定量标志物的表达情况,可以更准确地预测鼻咽癌患者的转移风险及预后,更好地指导临床用药。因此,定量标志物表达情况的试剂可以用于制备预测鼻咽癌患者的转移风险及预后试剂。特别的,定量标志物表达量的试剂选自核酸探针试剂。
本发明的有益效果是:
本发明13个基因表达构成的分子标签,可以反映鼻咽癌患者的生物学特异性,可以更准确地预测鼻咽癌患者的转移风险及预后,更好地指导临床用药,对无远处生存的预测效能要优于传统N分期。
附图说明
图1:K-M生存分析显示DMGN高风险组鼻咽癌患者无远处转移生存在(A)训练组,n=410,(B)内部验证组,n=204,(C)外部组1,n=165,和(D)外部组2n=158均较差;
图2:K-M生存分析显示DMGN高风险组鼻咽癌患者无疾病生存在(A)训练组,n=410,(B)内部验证组,n=204,(C)外部组1,n=165,和(D)外部组2n=158均较差;
图3:K-M生存分析显示DMGN高风险组鼻咽癌患者总生存在(A)训练组,n=410,(B)内部验证组,n=204,(C)外部组1,n=165,和(D)外部组2,n=158均较差;
图4:ROC曲线比较列线图,DMGN,性别,LDH,CRP,N分期对于局部晚期鼻咽癌患者无远处转移风险预测的敏感性和特异性;
图5:K-M生存分析显示DMGN高风险组鼻咽癌患者是否接受同期化疗的无远处转移生存(A)内部组中高风险患者,n=312,(B)内部组中低风险患者,n=302,(C)外部组中高风险患者1,n=183,和(D)外部组中低风险患者,n=140;
图6:预测局部晚期鼻咽癌无远处转移生存的线列图。
具体实施方式
下面结合实验,进一步说明本发明的技术方案。
病例筛选:
发明人选取了937例病人作为非转移性初治的局部晚期鼻咽癌患者的样本,这些患者病人都接受是经过了根治性放射性治疗。其中的56.6%的患者病人(530例)还接受过以顺铂为基础的同期化疗。经过68.1个月(四分位数IQR 44.6~84.4)其中209人在随访期间发生了转移。
发明人采用Affymetrix Human Gene 2.0ST表达谱芯片检测了24例高转移风险(初诊无转移,但在根治性治疗后2年内出现远处转移)和24例低转移风险(初诊无转移,且根治性治疗后随访5年未出现转移及复发)鼻咽癌患者的初诊活检石蜡组织标本,通过筛选得到137个差异表达基因。
鼻咽癌转移分子靶标的发现
发明人利用NanoString nCounter技术平台在训练组410例标本(来自中山大学肿瘤防治中心)中检测这137个差异表达基因和5个内参基因,筛选出与DMFS(无远处转移生存)最为相关的13个基因构建模型,发明人将这组13个基因构成的标志物命名为DMGN(distant metastasis gene signature for LA-NPC,局部晚期鼻咽癌基因标签),其计算公式为:
DMGN评分公式=(0.1846×YBX3表达量)-(0.3007×CBR3表达量)-(0.1383×CXCL10表达量)-(0.3661×CLASP1表达量)+(0.2381×DCTN1表达量)-(0.4004×FNDC3B表达量)+(0.6×WSB2表达量)+(0.1093×LRIG1表达量)-(0.1162×GRM4表达量)+(0.1327×ANXA1表达量)+(0.1485×WNK1表达量)+(0.0714×HDLBP表达量)+(0.1774×POLR2M表达量),式中,表达量没有单位,基于ACTB、B2M、PGK1、RPL19、RPLP0五个内参基因的几何均数进行计算。
用X-tile软件生成阈值为5.01,由此将203例(49.5%)患者分为高风险组,207例(50.5%)分为低风险组;这两组患者五年的无远处转移生存率在高风险组为63%(95%CI置信区间56.1-69.6),在低风险组为91%(95%置信区间85.9-94.2;HR风险比4.93,95%CI2.99-8.16;p<0.001;图1)。与低风险组患者相比,高风险组患者的无疾病生存(HR 3.51,95%CI 2.43-5.07;p<0.001;图2)和总生存(HR 3.22,95%CI 2.18-4.76;p<0.001;图3)均较差。
转移靶标的进一步验证
发明人随后在本院和两组外院样本中对这一组分子标签进行了验证。
在本院内部验证组的204例患者中,DMGN将99例(48.5%)患者分为高风险组,105例(51.5%)分为低风险组,与低风险组患者相比,高风险组患者的无远处转移生存(HR2.98,95%CI 1.60-5.55,p<0.001;图1),无疾病生存(HR 2.14,95%CI 1.30-3.54;p=0.002;图2)和总生存(HR 2.00,95%CI 1.22-3.27;p=0.005;图3)均较差。
在外部验证组1(桂林医学院附属肿瘤医院)的165例患者中,DMGN将99例(48.5%)患者分为高风险组,105例(51.5%)分为低风险组,与低风险组患者相比,高风险组患者的无远处转移生存(HR 2.98,95%CI 1.60-5.55,p<0.001;图1),无疾病生存(HR 2.14,95%CI 1.30-3.54;p=0.002;图2)和总生存(HR 2.00,95%CI 1.22-3.27;p=0.005;图3)均较差。同样,在外部验证组2(佛山市第一人民医院)的158例患者中,DMGN将63例(44.9%)患者分为高风险组,87例(55.1%)分为低风险组,与低风险组患者相比,高风险组患者的无远处转移生存(HR 3.62;95%CI 1.43-9.19;p=0.004;图1),无疾病生存(HR 3.10,95%CI1.48-6.47;p=0.002;图2)和总生存(HR 2.45,95%CI 1.19-5.02;p=0.012;图3)均较差。
发明人进一步进行了单因素和多因素Cox分析,在4组患者均显示DMGN为局部晚期鼻咽癌患者无远处转移生存的独立预后因素。此外,发明人还分析了DMGN是否能预测鼻咽癌患者对同期化疗的获益。在本院(中山大学肿瘤防治中心)的614例患者中,有326例患者接受了同期化疗,分析显示,低风险组的患者接受同期化疗后无远处转移生存得到显著改善(HR 0.40;95%CI 0.19-0.83;p=0.011;图5),而高风险组无统计学差异(HR 1.03;95%CI 0.71-1.50;p=0.876;图5),外部组的分析也验证了这一结论。
应用ROC(receiver operating characteristic,受试者工作特征)曲线下面积(AUC)评价指标的敏感性特异性,如图4所示,DMGN对无远处生存的预测效能要优于传统N分期。
为了提供一种可以预测是否有癌症转移风险的临床方法,发明人将13个基因最为临床判断的因素。根据多变量分析DMFS。发明人用列线图(Nomogram)预测在治疗组中的DMFS,这些预测因素包括DMGN,性别,N分期,LDH(乳酸脱氢酶)和CRP(C反应蛋白)表达水平,在这些因素中,DMGN有最高预测效能的C-index值0.673,根据五年DMFS预测值结果绘制预测曲线(caliberationcurve)在各组患者中均显示很高的一致性(图6),实验组1(C-index:0.727,95%CI 0.679-0.775,Figure 5),实验组2(C-index:0.725,95%CI 0.654-0.796),实验组3(Cindex:0.693,95%CI 0.617-0.769),实验组4(0.739,95%CI0.639-0.839)。ROC对灵敏度和特异性进行分析,DMGN预测效果要优于常用的临床风险评估因素(图4)。
Claims (9)
1.一组用于预测鼻咽癌转移风险的标志物,该组标志物包括ANXA1、CBR3、CLASP1、CXCL10、DCTN1、FNDC3B、LRIG1、FNDC3B、HDLBP、POLR2M、WSB2、WNK1、YBX3。
2.根据权利要求1所述的标志物,其特征在于:用于NPC风险预测的评分公式根据Cox风险比例模型确定。
3.根据权利要求1所述的标志物,其特征在于:用于NPC风险预测的评分公式为:分值=(0.1846×YBX3表达量)-(0.3007×CBR3表达量)-(0.1383×CXCL10表达量)-(0.3661×CLASP1表达量)+(0.2381×DCTN1表达量)-(0.4004×FNDC3B表达量)+(0.6×WSB2表达量)+(0.1093×LRIG1表达量)-(0.1162×GRM4表达量)+(0.1327×ANXA1表达量)+(0.1485×WNK1表达量)+(0.0714×HDLBP表达量)+(0.1774×POLR2M表达量)。
4.根据权利要求1或3所述的标志物,其特征在于:用于确定标志物相对表达量的内参基因选自ACTB、B2M、PGK1、RPL19、RPLP0。
5.定量标志物或其产物表达量的试剂在制备鼻咽癌转移风险检测试剂中的应用,其特征在于:标志物如权利要求1所述。
6.根据权利要求5所述的应用,其特征在于:定量标志物表达量的试剂选自核酸探针试剂。
7.根据权利要求5所述的应用,其特征在于:用于NPC风险预测的评分公式根据Cox风险比例模型确定。
8.根据权利要求5所述的应用,其特征在于:用于NPC风险预测的评分公式为:分值=(0.1846×YBX3表达量)-(0.3007×CBR3表达量)-(0.1383×CXCL10表达量)-(0.3661×CLASP1表达量)+(0.2381×DCTN1表达量)-(0.4004×FNDC3B表达量)+(0.6×WSB2表达量)+(0.1093×LRIG1表达量)-(0.1162×GRM4表达量)+(0.1327×ANXA1表达量)+(0.1485×WNK1表达量)+(0.0714×HDLBP表达量)+(0.1774×POLR2M表达量)。
9.根据权利要求5所述的应用,其特征在于:用于确定标志物相对表达量的内参基因选自ACTB、B2M、PGK1、RPL19、RPLP0。
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