CN113564258A - Ptprd基因突变在预测tp53突变型肺癌患者免疫治疗敏感性中的应用 - Google Patents

Ptprd基因突变在预测tp53突变型肺癌患者免疫治疗敏感性中的应用 Download PDF

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CN113564258A
CN113564258A CN202110984444.3A CN202110984444A CN113564258A CN 113564258 A CN113564258 A CN 113564258A CN 202110984444 A CN202110984444 A CN 202110984444A CN 113564258 A CN113564258 A CN 113564258A
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lung cancer
ptprd
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董忠谊
吴德华
白雪
蔡晓庭
谭家乐
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Abstract

本发明涉及基因突变在预测肺癌患者免疫治疗敏感性中的应用，具体涉及了PTPRD基因突变在预测TP53突变型肺癌患者免疫治疗敏感性中的应用以及PTPRD基因突变的检测产品在制备预测TP53突变型肺癌患者对免疫检查点抑制剂疗法敏感性产品中的应用，所述PTPRD基因突变的存在为TP53突变型肺癌患者对免疫检查点抑制剂疗法敏感的指征。本发明筛选出PTRPD突变基因作为预测TP53突变型肺癌患者中对ICI敏感的群体生物标志物；通过PTRPD突变，能够预测TP53突变型肺癌患者肿瘤淋巴细胞浸润和PD‑L1表达高低，进而预测ICI敏感的群体，精确筛选更多免疫治疗获益人群。

Description

PTPRD基因突变在预测TP53突变型肺癌患者免疫治疗敏感性 中的应用
技术领域
本发明涉及基因突变在预测肺癌患者免疫治疗敏感性中的应用，具体涉及了PTPRD基因突变在预测TP53突变型肺癌患者免疫治疗敏感性中的应用。
背景技术
肺癌是人类最常见的恶性肿瘤。肺癌的发生发展与驱动基因变异密切相关，基于驱动基因变异所衍生的分子靶向治疗在肺癌治疗上取得重大突破。然而耐药问题的出现，限制了患者的持续受益。近年来随着免疫治疗的兴起，越来越多的研究发现，在肺癌中驱动基因变异与免疫治疗耐药有着内在关联，如EGFR突变NSCLC患者免疫治疗疗效下降，TP53/KRAS突变则显著增加免疫治疗疗效。既往的研究已经证明，PD-L1表达、肿瘤突变负荷(tumor mutation burden,TMB)、微卫星不稳定(Microsatellite instability,MSI)及肿瘤浸润淋巴细胞(Tumorinfiltrating lymphocytes,TIL)等可以有效预测免疫治疗疗效。但这些预测因子仍存在一些问题：如预测效能、肿瘤异质性、瘤种特异性等。因此，目前关键问题仍集中在如何筛选有效预测标志物以提高免疫治疗获益人群。
TP53基因突变是人类多种肿瘤最常见的驱动基因，在NSCLC中TP53突变率高达60％以上。TP53突变肿瘤在发病机制及治疗上都非常复杂，既往研究表明肺癌中TP53突变相较于其他肺癌常见驱动突变具有更高的TMB和更高的PD-L1表达，免疫基因表达谱分析显示TP53突变肿瘤相较于TP53野生型肿瘤，细胞毒活性相关基因表达显著升高。这些结果提示TP53突变肿瘤可能是一类对ICIs治疗相对敏感的肿瘤，然而目前针对TP53突变型NSCLC仍未有有效治疗手段。因此，寻找合适的预测标志物，对为TP53突变型NSCLC提供有效免疫干预措施具有重要意义。
发明内容
针对上述问题，本发明的目的是提供PTPRD基因突变在预测TP53突变型肺癌患者免疫治疗敏感性中的应用。
为实现上述目的，本发明提供的技术方案如下：
本发明提供一种PTPRD基因突变作为生物标志物在预测TP53突变型肺癌患者对免疫检查点抑制剂疗法敏感性中的应用。
本发明还提供一种PTPRD基因突变的检测产品在制备预测TP53突变型肺癌患者对免疫检查点抑制剂疗法敏感性产品中的应用，PTPRD基因突变的存在为TP53突变型肺癌患者对免疫检查点抑制剂疗法敏感的指征。
进一步地，所述PTPRD基因突变的存在为TP53突变型肺癌患者对免疫检查点抑制剂疗法敏感的指征通过对TP53基因突变型肺癌肿瘤组织进行基因突变的检测得到，若PTPRD基因存在基因突变，则患者对对免疫检查点抑制剂疗法敏感度高。
进一步地，所述检测以ctDNA、肿瘤组织或肿瘤循环细胞为检测样品。
进一步地，所述检测以基因测序、PCR、FISH、免疫组化、ELISA、Western或流式细胞技术为检测方法。
进一步地，所述免疫检查点抑制剂为PD1抑制剂和/或PDL1抑制剂。
进一步地，所述突变为点突变；
更进一步地，所述点突变包括但不限于单核苷酸多态性，碱基取代/插入/缺失，或沉默突变。
与现有技术相比，本发明的有益效果为：
1.本发明筛选出PTRPD突变基因作为预测TP53突变型肺癌患者中对ICI敏感的群体生物标志物；通过PTRPD突变，能够预测TP53突变型肺癌患者肿瘤淋巴细胞浸润和PD-L1表达高低，进而预测ICI敏感的群体，精确筛选更多免疫治疗获益人群。
2.本发明采用的PTPRD基因突变在实际应用中可作为预测风险因素，提高检测效率，结果更为可靠。
附图说明
图1为本发明实施例中TP53突变型NSCLC患者中伴随基因突变发生频率最高的7个基因；
图2为本发明实施例中TP53突变与野生NSCLC患者免疫治疗差异(A)以及TP53突变合并其他不同共突变基因接受anti-PD-1/PD-L1免疫治疗后总生存的差异(B)；
图3为本发明实施例中不同TP53及PTPRD突变状态分组的NSCLC患者免疫治疗无进展生存(A)及总生存(B)的差异；
图4为本发明实施例中TP53突变/PTPRD突变双突变与TP53突变/PTPRD野生在(A)STING信号通路及(B)IFN-β信号通路的基因富集分析(GESA)的结果；不同TP53及PTPRD突变状态分组中STING信号通路两个关键基因(C)STING1和(D)IRF3 RNA的表达；
图5为本发明不同TP53及PTPRD突变状态分组下(A)CD8A及(B)PD-L1 RNA表达的差异；(C)TP53及PTPRD突变状态对的免疫微环境4种构成(PD-L1/CD8A阳性比例分布)的影响；
图6为本发明实施例中不同TP53及PTPRD突变状态分组的NSCLC患者的肿瘤突变负荷TMB分数；
图7为本发明实施例中PTPRD基因突变位点分析图。
具体实施方式
为了更好的说明本发明的目的、技术方案和优点，下面将结合附图和具体实施例对本发明作进一步说明。
实施例1
PTPRD基因突变作为生物标志物在预测TP53突变型肺癌患者对免疫检查点抑制剂疗法敏感性中的应用。
本实施例通过对MSK癌症中心348例接受免疫治疗NSCLC患者的DNA进行测序，其结果分析如图1所示。其中，TP53突变率为62.1％(216/348)。图1为TP53突变型NSCLC患者中伴随基因突变发生频率最高的7个基因，这216例TP53突变型患者按照共突变基因发生频率高低依次为KRAS(25.9％)、KEAP1(19.4％)、PTPRD(15.7％)、EGFR(14.8％)、STK11(13.4％)、PTPRT(13.0％)及SMARCA4(9.3％)。
对TP53突变患者进行多因素Cox回归分析，筛选与TP53突变型肺癌免疫治疗显著效果的独立预后基因，纳入指标包括上述7个与TP53伴随突变的高频突变基因(KRAS、KEAP1、PTPRD、EGFR、STK11、PTPRT及SMARCA4)，采用backward:conditional法。最后结果显示，仅PTPRD突变可以作为TP53突变型NSCLC接受免疫治疗独立预测因素(HR＝1.848；P＝0.025)，结果见表1
表1
Figure BDA0003230256280000051
通过Kaplan–Meier生产曲线分析，发现单纯TP53突变与野生型NSCLC对免疫治疗疗效相当(图2A)。进一步探讨TP53合并不同共突变基因接受anti-PD-1/PD-L1免疫治疗后总生存的差异，结果显示，TP53/PTPRD双突变组OS显著优于其他伴随突变亚组(图2B)。
对队列总人群按照TP53及PTPRD突变状态进行亚组分析。
各小组患者特征表征如表2所示。性别、年龄、病理类型和用药在TP53野生组内和TP53突变组内均与PTPRD状态无显著相关性。在TP53野生组和突变组内，TMB与PTPRD状态均有显著相关性，PTPRD突变型的TMB均显著高于PTPRD野生型的TMB(TP53野生组：p<0.001；TP53突变组：p<0.001)。
表2 NSCLC患者特征
Figure BDA0003230256280000061
为了进一步明确TP53/PTPRD双突变是否为NSCLC患者免疫治疗优势人群，本发明分析了不同TP53及PTPRD突变状态的NSCLC患者免疫治疗无进展生存(PFS，图3A)及总生存(OS，图3B)的差异。对PFS和OS进行亚组分析(TP53突变PTPRD突变vs.TP53突变PTPRD野生vs.TP53野生PTPRD突变vs.TP53野生PTPRD野生)，无论是PFS(P＝0.004)还是OS(P＝0.012)分析，TP53/PTPRD双突变组相较于其他亚组均显著提高NSCLC患者免疫治疗疗效。
实施例2
TP53突变型NSCLC患者PTPRD基因突变对免疫微环境的影响
为了阐明TP53/PTPRD双突变患者免疫治疗疗效显著的内在因素，本发明通过基因集富集分析(gene set enrichment analysis，GSEA)方法，分析肺癌TCGA(The CancerGenome Atlas)数据库中TP53及PTPRD基因突变状态对基因富集信号通路的影响，结果如图4所示。通过图4A、4B可知，TP53突变/PTPRD突变双突变组相较于TP53突变/PTPRD野生组显著上调干扰素基因刺激因子(cGAS-STING)信号通路及IFN-β信号通。此外，图4C、4D可以看出，肺癌TCGA数据库分析显示TP53突变/PTPRD突变组相较于其他亚组STING1及其下游关键基因IRF3的RNA表达显著高表达，这说明PTPRD缺失突变能够激活cGAS-STING信号通路调节固有免疫。
为了明确TP53/PTPRD双突变对肺癌患者免疫微环境的影响，本发明分析了TCGA肺癌数据库中CD8A及PD-L1 RNA的表达；并进一步探讨TP53及PTPRD不同突变状态对的免疫微环境4种构成(PD-L1/CD8A阳性比例分布)的影响。
结果显示：TP53/PTPRD双突变组相较于其他亚组CD8A RNA表达水平显著增高，进一步提示PTPRD缺失突变可能诱导肿瘤浸润淋巴细胞增加(图5A)。
肿瘤组织中PD-L1表达已被证实可以预测anti-PD-1/PD-L1免疫治疗疗效。进一步分析TCGA肺癌数据库中RNA表达谱，从图5B的结果显示，TP53/PTPRD双突变组PD-L1 RNA表达水平均显著高于其他亚组。
既往研究根据PD-L1与TIL的不同表达状态将肿瘤免疫微环境分为四种类型。因而通过分析TCGA肺癌数据库中PD-L1/CD8A阳性比例分布来反映肿瘤免疫微环境分类。结果显示TP53/PTPRD双突变组中PDL1+/CD8A+双阳性比例显著高于其他亚组，而PD-L1-/CD8A-双阴性比例则显著低于其他亚组(图5C)。
此外，既往研究还表明，肿瘤免疫治疗疗效与肿瘤突变负荷(TMB)显著相关。因此，我们还进一步探讨TP53/PTPRD双突变是否与肺癌患者TMB的相关。图6为不同TP53及PTPRD突变状态分组的NSCLC患者的TMB分数，结果显示TMB在TP53/PTPRD双突变组显著高于其他三个亚组。
上述结果表明，PTPRD基因突变一方面能够促进肿瘤内淋巴细胞浸润和免疫检查点分子PD-L1表达，进而激活免疫炎症型肿瘤微环境，另一方面通过增加肿瘤突变负荷，导致肿瘤新抗原产生，进而发挥抗肿瘤免疫功能，从而提高免疫治疗疗效。
实施例3PTPRD基因突变位点分析
对PTPRD基因突变位点进行分析，结果如图7所示。发现PTPRD基因变异形式主要为错义突变，其次为截断突变和整码突变。基因变异位点比较分散，没有明显的热点突变区域。
综上所述，PTPRD基因突变可作为TP53突变型肺癌患者对免疫检查点抑制剂疗法敏感性的预测因子。
虽然本发明是通过优选的具体实施例进行说明，但是对于本领域的技术人员来说，本发明可以有各种更改和变化。凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (8)

1.PTPRD基因作为生物标志物在预测TP53突变型肺癌患者对免疫检查点抑制剂疗法敏感性中的应用。
2.PTPRD基因突变的检测产品在制备预测TP53突变型肺癌患者对免疫检查点抑制剂疗法敏感性产品中的应用，其特征在于，所述PTPRD基因突变的存在为TP53突变型肺癌患者对免疫检查点抑制剂疗法敏感的指征。
3.根据权利要求2所述的应用，其特征在于，所述PTPRD基因突变的存在为TP53突变型肺癌患者对免疫检查点抑制剂疗法敏感的指征通过对TP53基因突变型肺癌肿瘤组织进行基因突变的检测得到，若PTPRD基因存在基因突变，则患者对对免疫检查点抑制剂疗法敏感度高。
4.根据权利要求3所述的应用，其特征在于，所述检测以ctDNA、肿瘤组织或肿瘤循环细胞为检测样品。
5.根据权利要求6所述的应用，其特征在于，所述检测以基因测序、PCR、FISH、免疫组化、ELISA、Western或流式细胞技术为检测方法。
6.根据权利要求1或2所述的应用，其特征在于，所述免疫检查点抑制剂为PD1抑制剂和/或PDL1抑制剂。
7.根据权利要求6所述的应用，其特征在于，所述突变为点突变。
8.根据权利要求7所述的应用，其特征在于，所述点突变包括但不限于单核苷酸多态性、碱基取代/插入/缺失或沉默突变。
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