背景:越来越多的证据表明TP53突变在癌症中的免疫调节和环境依赖性作用。我们对转录进行了探索性分析,结直肠癌(CRC)基于基因表达的共有分子亚型(CMSs)内TP53突变的免疫生物学和预后相关性。
方法:在401个I-IV期初级CRC的单医院系列中,我们对TP53的整个编码区进行了测序,并通过基因表达谱分析分析了突变的CMS依赖性转录后果。免疫调节关联通过多重验证,基于荧光的免疫细胞标记的免疫组织化学。在根据CMS分类的635例患者中分析了TP53突变的预后关联。包括来自法国多中心队列(GSE39582)的公开数据。
结果:在60%的CRC中发现TP53突变。然而,基因集富集分析表明,它们的转录后果在CMSs之间有所不同,在CMS1免疫和CMS4间充质中最为明显。亚型特异性主要被视为反映CMS4中细胞周期进程的基因集的上调和CMS1中T细胞活性的下调。与仅在CMS1中的野生型(wt)肿瘤相比,突变肿瘤中几种免疫细胞群的显着消耗增强了亚型依赖性免疫调节关联,包括细胞毒性淋巴细胞(CMS1中调整的p值=0.002和CMS2-4>0.9,微环境细胞群(MCP)-计数器算法)。这通过基于免疫组织化学的肿瘤浸润CD8+细胞的定量来验证。在CMS1中,TP53突变的免疫调节关联在微卫星稳定(MSS)肿瘤中最强,这转化为转移性疾病的倾向和CMS1/MSS亚型突变的不良预后价值(两个系列的总生存期:TP53突变vswt:HR5.52,p=0.028)。
结论:在原发性CRC中,TP53突变状态与CMS框架的整合表明亚型依赖性免疫生物学与预后和潜在的免疫治疗相关。保证独立验证。
BACKGROUND: Accumulating evidence suggests immunomodulatory and context-dependent effects of TP53 mutations in cancer. We performed an exploratory analysis of the transcriptional, immunobiological and prognostic associations of TP53 mutations within the gene expression-based
consensus molecular subtypes (CMSs) of colorectal cancer (CRC).
METHODS: In a single-hospital series of 401 stage I-IV primary CRCs, we sequenced the whole coding region of TP53 and analysed CMS-dependent transcriptional consequences of the mutations by gene expression profiling. Immunomodulatory associations were validated by multiplex, fluorescence-based immunohistochemistry of immune cell markers. Prognostic associations of TP53 mutations were analysed in an aggregated series of 635 patients classified according to CMS, including publicly available data from a French multicentre cohort (GSE39582).
RESULTS: TP53 mutations were found in 60% of the CRCs. However, gene set enrichment analyses indicated that their transcriptional consequences varied among the CMSs and were most pronounced in CMS1-immune and CMS4-mesenchymal. Subtype specificity was primarily seen as an upregulation of gene sets reflecting cell cycle progression in CMS4 and a downregulation of T cell activity in CMS1. The subtype-dependent immunomodulatory associations were reinforced by significant depletion of several immune cell populations in mutated tumours compared with wild-type (wt) tumours exclusively in CMS1, including cytotoxic lymphocytes (adjusted p value in CMS1=0.002 and CMS2-4>0.9, Microenvironment Cell Populations (MCP)-counter algorithm). This was validated by immunohistochemistry-based quantification of tumour infiltrating CD8+ cells. Within CMS1, the immunomodulatory association of TP53 mutations was strongest among microsatellite stable (MSS) tumours, and this translated into a propensity for metastatic disease and poor prognostic value of the mutations specifically in the CMS1/MSS subtype (both series overall survival: TP53 mutation vs wt: HR 5.52, p=0.028).
CONCLUSIONS: Integration of TP53 mutation status with the CMS framework in primary CRC suggested subtype-dependent immunobiological associations with prognostic and potentially immunotherapeutic implications, warranting independent validation.