CN109609641B - 一种针对asmt/cyp1a2分子的试剂盒在预测实体瘤临床预后和免疫特征中的应用 - Google Patents

一种针对asmt/cyp1a2分子的试剂盒在预测实体瘤临床预后和免疫特征中的应用 Download PDF

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CN109609641B
CN109609641B CN201910041894.1A CN201910041894A CN109609641B CN 109609641 B CN109609641 B CN 109609641B CN 201910041894 A CN201910041894 A CN 201910041894A CN 109609641 B CN109609641 B CN 109609641B
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孙颖
陈雨沛
吕佳蔚
郑子奇
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Abstract

本发明公开了一种针对ASMT/CYP1A2分子的试剂盒在预测实体瘤临床预后和免疫特征中的应用。发明人通过研究14种实体肿瘤共6658份肿瘤样本的转录组及基因组数据，进行大样本的生物信息分析，证实了ASMT/CYP1A2的比值水平在不同实体肿瘤中与患者的临床预后、肿瘤突变水平、肿瘤新生抗原负荷的关系。其中，High Index组的乳腺癌、胃癌患者临床预后更为可观，多因素分析结果显示，ASMT/CYP1A2的结果是肿瘤患者临床预后独立预测指标；另外，在膀胱癌、乳腺癌、前列腺癌患者中，Low Index组患者的预后虽然较差，但存在更多的突变负荷和/或肿瘤新生抗原，提示该组患者更有可能从免疫治疗中获益。

Description

一种针对ASMT/CYP1A2分子的试剂盒在预测实体瘤临床预后 和免疫特征中的应用
技术领域
本发明涉及预测实体肿瘤的临床预后及免疫体突变水平和/或新抗原负荷的标志物及应用。
背景技术
肿瘤是威胁人类健康的第三大疾病。2018年，全球约有1819万癌症新增病例以及960万癌症死亡病例。肿瘤的发生率随着医学技术的进步、人们防癌意识的增强呈现逐年下降的趋势，而部分癌种的死亡率仍然居高不下。因此准确地评估肿瘤患者的预测情况，并根据其特点选择合适的治疗方案至关重要。近年来，免疫治疗发展迅猛，成为继手术，放化疗、靶向治疗后的第四大抗癌武器。相关免疫治疗药物，如抗PD-1单抗Nivolumab和Pembrolizumab等均在多个癌种中证实有效，并已被美国FDA获批用于黑色素瘤、肺癌、头颈部肿瘤等患者的治疗。然而免疫治疗仅对部分患者有效，亟需特异性的生物标志物能够筛选合适的肿瘤患者接受免疫治疗，提高治疗获益。目前在多种肿瘤中已经被证实有效的预测指标包括：体突变水平及新抗原水平。
褪黑素(Melatonin)最早是由Lemer等人分离出的能够使皮肤变白的吲哚类物质，并将其命名为褪黑素。在哺乳动物和人类，它是由松果体产生的一种胺类激素，能为机体提供时间信息，确保昼夜节律及季节节律同步。因此，褪黑素在人体的表达也呈周期性变化。根据既往报道的文献，褪黑素具有抗肿瘤作用。例如，褪黑素可通过减少αvβ3整合素的表达水平，抑制胶质瘤细胞向周围微环境的迁移能力。另外，褪黑素可通过下调乳腺癌组织中抗脂肪细胞因子的表达，减少肿瘤组织的周围成纤维细胞和内皮细胞的数量，进而促进乳腺癌的转移。同时，研究结果表明，褪黑素在实体瘤的发生、发展、机体的免疫状态调节等方面起重要的作用。例如，褪黑素可通过修复DNA损伤从而抑制乳腺癌的发生和异常乳腺肿瘤细胞的增殖；此外，人体褪黑素可促进多种免疫细胞的活化、抗原呈递过程等进而调节免疫反应。
虽然理论研究上肿瘤患者的褪黑素微环境及其作用在临床的应用具有良好的前景。但是，由于褪黑素分泌的周期性(节律性)，外周血检测得到的褪黑素水平往往无法准确反应患者肿瘤褪黑素微环境的水平和特征。其次，褪黑素的合成和代谢受多种酶的影响，其合成和代谢网络相对复杂。考虑到患者体内褪黑素合成及代谢生物酶的功能及表达量在时间和空间上与肿瘤褪黑素微环境本身相对分离，实际临床应用中，普遍认为难以基于患者体内褪黑素的水平有效预测实体肿瘤的临床预后和/或免疫体突变水平和/或新抗原特征。因此，在肿瘤组织中寻找可反映肿瘤微环境中褪黑素水平高低的标志物具有重要的临床应用价值。然而，目前尚没有相关应用的分子标签。
发明内容
本发明的目的在于提供分子标志物ASMT/CYP1A2的临床应用，通过其描绘肿瘤褪黑素微环境，并有效预测实体肿瘤的临床预后及免疫体突变水平和/或新生抗原负荷。
发明人通过研究发现，通过计算ASMT和CYP1A2表达量的比值描绘肿瘤褪黑素微环境，可有效对实体肿瘤患者的肿瘤褪黑素微环境进行分型，通过median中位值将其分为High Index跟Low Index组。通过对公共数据库“癌症基因组图谱(The Cancer GenomeAtlas,TCGA)”中14种实体肿瘤(膀胱癌、乳腺癌、宫颈癌、结肠癌、头颈鳞癌、肾癌、肝细胞癌、肺腺癌、肺鳞癌、胰腺癌、前列腺癌、皮肤癌、胃癌和甲状腺癌)共6658份肿瘤样本的转录组及基因组数据，进行大样本的生物信息分析，证实了ASMT/CYP1A2的比值水平在不同实体肿瘤中与患者的临床预后、肿瘤突变水平、肿瘤新生抗原负荷的关系。其中，High Index组的乳腺癌和胃癌患者临床预后更为可观，多因素分析结果显示，ASMT/CYP1A2的结果是肿瘤患者临床预后独立预测指标；另外，在膀胱癌、乳腺癌、前列腺癌患者中，Low Index组患者的预后虽然较差，但存在更多的突变负荷和肿瘤新生抗原，提示该组患者更有可能从免疫治疗中获益。
本发明所采取的技术方案是：
确定ASMT和CYP1A2表达量比值的试剂盒在制备预测实体肿瘤临床预后试剂盒中的应用。
作为上述应用的进一步改进，实体肿瘤选自乳腺癌、胃癌肿瘤。
确定ASMT和CYP1A2表达量比值的试剂盒在制备预测实体肿瘤免疫体突变水平和/或抗原负荷试剂盒中的应用。
作为上述应用的进一步改进，实体肿瘤选自：膀胱癌、乳腺癌、前列腺癌。
作为上述应用的进一步改进，ASMT和CYP1A2表达量为其mRNA的表达量。
作为上述应用的进一步改进，ASMT和CYP1A2表达量为实体肿瘤中的表达量。
作为上述应用的进一步改进，确定ASMT和CYP1A2表达量比值的试剂盒为检测ASMT和CYP1A2mRNA表达量的试剂盒。
本发明的有益效果是：
本发明方法，通过计算ASMT和CYP1A2表达量的比值描绘肿瘤的褪黑素微环境，可以有效预测实体肿瘤中不同组患者的临床预后及免疫体突变水平和新抗原特征，指导临床用药，提高治疗效果。特别是可有效预测乳腺癌、胃癌患者的临床预后及膀胱癌、乳腺癌、前列腺癌患者的免疫体突变水平和/或新抗原特征，并进一步预测其可能的免疫治疗获益。
附图说明
图1是TCGA数据库中，14种实体肿瘤(膀胱癌、乳腺癌、宫颈癌、结肠癌、头颈鳞癌、肾癌、肝细胞癌、肺腺癌、肺鳞癌、胰腺癌、前列腺癌、皮肤癌、胃癌和甲状腺癌)的ASMT/CYP1A2水平；
图2～5是TCGA数据库中，乳腺癌、胃癌患者组织中High Index与Low Index组的总生存(Overall survival,OS)情况；
图6是TCGA数据库中，膀胱癌、乳腺癌、前列腺癌患者组织中High Index与LowIndex组的突变水平；
图7是TCGA数据库中，膀胱癌、乳腺癌、前列腺癌患者组织中High Index与LowIndex组的新生抗原负荷(结直肠癌和胰腺癌由于没有足够的新生抗原的数据而被排除)；
具体实施方式
下面结合具体实验进一步阐述本发明，应理解，以下内容仅用于说明本发明而不用于限制本发明的保护范围。
不同实体肿瘤中的ASMT/CYP1A2比值情况
通过分析公共数据库TCGA中14种实体肿瘤(膀胱癌、乳腺癌、宫颈癌、结肠癌、头颈鳞癌、肾癌、肝细胞癌、肺腺癌、肺鳞癌、胰腺癌、前列腺癌、皮肤癌、胃癌和甲状腺癌)共6,658份肿瘤样本的转录组及基因组数据，计算每种肿瘤组织中ASMT与CYP1A2的比值(ASMT/CYP1A2)，该比值反应该肿瘤组织中褪黑素水平的高低。将每种肿瘤组织ASMT/CYP1A2的结果按照其中位数分为High Index和Low Index(图1)组。
不同实体肿瘤中的ASMT/CYP1A2比值与临床预后的关系
Kaplan–Meier生存分析及Cox proportional hazards多因素模型的结果均显示：在乳腺癌、胃癌肿瘤中，High Index组患者的总生存期更长，具有更良好的临床预后，可作为肿瘤患者临床预后的独立预测指标(图2～图5)。在均衡了性别，年龄，种族，肿瘤分期等重要因素后，High Index组乳腺癌患者的总生存(overall survival)显著高于Low index组患者的总生存，差异有统计学意义(调整风险比[adjusted hazard ratio,AHR]＝0.65；95％置信区间(confidence interval,CI)＝0.44–0.97；P＝0.03)。同样地，胃癌(AHR＝0.69；95％CI＝0.49–0.97,P＝0.03)患者中High index组患者的生存也明显好于Lowindex组患者。此外，High Index组在膀胱癌、宫颈癌、肺癌等患者中未观察到明显的生存优势。说明该分子标签也有其特异性，对特定的实体肿瘤具有很好的预测作用。
不同实体肿瘤中的ASMT/CYP1A2比值与免疫特征的关系
松果体和机体免疫系统之间也存在着密切的生理联系，提示肿瘤微环境中的褪黑素水平可能影响肿瘤患者的免疫特征及治疗疗效。越来越多的研究表明：不同肿瘤中突变水平及肿瘤新生抗原负荷可以作为免疫疗法疗效的预测指标。因此，我们对比了不同肿瘤褪黑素微环境下(High Index对比Low Index组)的突变水平及肿瘤新生抗原的负荷，发现在乳腺癌、前列腺癌患者组织中，Low Index组的肿瘤患者具有更高的突变水平(P<0.05)(图6)；在膀胱癌、前列腺癌患者组织中，Low Index组的肿瘤患者具有高的肿瘤新生抗原负荷(P<0.05)(图7)。而宫颈癌、肺癌、胃癌等患者中则未观察到High index对比Low index组具有明显的突变水平和/或肿瘤新生抗原负荷的差异。

Claims (12)

1.确定ASMT和CYP1A2表达量比值的试剂在制备预测实体肿瘤临床预后试剂盒中的应用；
所述实体肿瘤选自乳腺癌和胃癌。
2.根据权利要求1所述的应用，其特征在于：
ASMT和CYP1A2表达量为ASMT和CYP1A2 mRNA的表达量。
3.根据权利要求2所述的应用，其特征在于：
ASMT和CYP1A2表达量为实体肿瘤中的表达量。
4.根据权利要求1所述的应用，其特征在于：
确定ASMT和CYP1A2表达量比值的试剂为检测ASMT和CYP1A2 mRNA表达量的试剂。
5.确定ASMT和CYP1A2表达量比值的试剂在制备预测实体肿瘤免疫体突变水平试剂盒中的应用；
所述实体肿瘤选自乳腺癌和前列腺癌。
6.根据权利要求5所述的应用，其特征在于：
ASMT和CYP1A2表达量为ASMT和CYP1A2 mRNA的表达量。
7.根据权利要求6所述的应用，其特征在于：
ASMT和CYP1A2表达量为实体肿瘤中的表达量。
8.根据权利要求5所述的应用，其特征在于：
确定ASMT和CYP1A2表达量比值的试剂为检测ASMT和CYP1A2 mRNA表达量的试剂。
9.确定ASMT和CYP1A2表达量比值的试剂盒在制备预测实体肿瘤抗原负荷试剂盒中的应用；
所述实体瘤选自膀胱癌和前列腺癌。
10.根据权利要求9所述的应用，其特征在于：ASMT和CYP1A2表达量为ASMT和CYP1A2mRNA的表达量。
11.根据权利要求10所述的应用，其特征在于：ASMT和CYP1A2表达量为实体肿瘤中的表达量。
12.根据权利要求9所述的应用，其特征在于：确定ASMT和CYP1A2表达量比值的试剂为检测ASMT和CYP1A2 mRNA表达量的试剂。
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