Ning Gang, Li Yongqiang, Chen Wenji, Tang Wenjuan, Shou Diwen, Luo Qingling, Chen Huiting, Zhou Yongjian
Department of Gastroenterology and Hepatology, Guangzhou Digestive Diseases Center, Guangzhou First People's Hospital, South China University of Technology, Guangzhou, Guangdong Province, China.
J Oncol. 2021 Nov 28;2021:2715694. doi: 10.1155/2021/2715694. eCollection 2021.
CpG island methylator phenotype (CIMP), featured with concurrent and widespread hypermethylation of a cluster of CpGs, has been reported to play an important role in carcinogenesis. Limited studies have investigated the role of CIMP in pancreatic cancer (PC). The aim of this study was to explore the CIMP in PC patients and its impact on the immune response of the tumor microenvironment and prognosis.
DNA methylation, somatic mutation, mRNA, and corresponding clinical data of PC patients were downloaded from TCGA (184 patients) and the ICGC (264 patients). Univariate and multivariate regression analyses were used to identify prognosis-related CpGs. Consensus clustering analysis was used for identification of the CIMP in PC patients. ESTIMATE and CIBORORT were used for estimation of the tumor microenvironment (TME) in PC patients.
In the TCGA PC cohort, 22,450 differential CpGs, including 12,937 hypermethylated CpGs and 9,513 hypomethylated CpGs, were identified between 184 PC patients and 10 normal controls. Univariate and multivariate Cox analysis further screened out 72 OS-related CpGs, and three distinct CIMP groups with distinctly different prognosis and molecular features, including the CIMP-L subgroup, CIMP-M subgroup, and CIMP-H subgroup, were identified based on unsupervised consensus clustering analysis of these CpGs. Patients of the CIMP-H subgroup had poorer OS and RFS, while patients of the CIMP-L subgroup had better OS and RFS. The CIMP status was also an independent prognostic factor for OS and PFS. In molecular features, significantly higher somatic mutation burden and tumor mutational burden were found in patients of the CIMP-H subgroup compared to those of the CIMP-L subgroup. Besides, lower stromal score, immune score, and higher cancer stemness indices and tumor purity were also found in patients of the CIMP-H subgroup compared to those of the CIMP-L subgroup. Correspondingly, significant total T cells, total B cells, CD8 T cells, memory CD4 T cells, and higher regulatory T cells were found in patients of the CIMP-H subgroup. Moreover, significantly lower expression of immune checkpoint genes, such as PD-1, CTLA4, CD86, VTCN1, and LAG-3, was also found in patients of the CIMP-H subgroup compared to those of the CIMP-L subgroup. In the end, we validated the CIMP status in PC patients of the ICGC dataset.
The CIMP may modulate the immune response of the tumor microenvironment and influence the prognosis of pancreatic cancer patients, which may help to make an assertion to provide specific and efficient treatment options for patients of different subtypes.
CpG岛甲基化表型（CIMP）以一组CpG位点同时发生广泛的高甲基化为特征，据报道在致癌过程中起重要作用。关于CIMP在胰腺癌（PC）中的作用的研究有限。本研究的目的是探讨PC患者中的CIMP及其对肿瘤微环境免疫反应和预后的影响。
从TCGA（184例患者）和ICGC（264例患者）下载PC患者的DNA甲基化、体细胞突变、mRNA及相应临床数据。采用单因素和多因素回归分析确定与预后相关的CpG位点。采用共识聚类分析确定PC患者中的CIMP。采用ESTIMATE和CIBORORT评估PC患者的肿瘤微环境（TME）。
在TCGA的PC队列中，在184例PC患者和10例正常对照之间鉴定出22,450个差异CpG位点，包括12,937个高甲基化CpG位点和9,513个低甲基化CpG位点。单因素和多因素Cox分析进一步筛选出72个与总生存期（OS）相关的CpG位点，并基于对这些CpG位点的无监督共识聚类分析，确定了三个具有明显不同预后和分子特征的不同CIMP组，包括CIMP-L亚组、CIMP-M亚组和CIMP-H亚组。CIMP-H亚组的患者OS和无复发生存期（RFS）较差，而CIMP-L亚组的患者OS和RFS较好。CIMP状态也是OS和无进展生存期（PFS）的独立预后因素。在分子特征方面，与CIMP-L亚组相比，CIMP-H亚组患者的体细胞突变负担和肿瘤突变负担明显更高。此外，与CIMP-L亚组相比，CIMP-H亚组患者的基质评分、免疫评分更低，癌症干性指数和肿瘤纯度更高。相应地，CIMP-H亚组患者的总T细胞、总B细胞、CD8 T细胞、记忆CD4 T细胞显著增加，调节性T细胞更高。此外，与CIMP-L亚组相比，CIMP-H亚组患者免疫检查点基因如PD-1、CTLA4、CD86、VTCN1和LAG-3的表达也显著降低。最后，我们在ICGC数据集的PC患者中验证了CIMP状态。
CIMP可能调节肿瘤微环境的免疫反应并影响胰腺癌患者的预后，这可能有助于为不同亚型的患者提供具体有效的治疗方案。
