Department of Thyroid and Neck Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China.
Department of Thyroid and Breast Surgery, Tianjin Union Medical Center, Tianjin, China.
Front Endocrinol (Lausanne). 2022 Oct 24;13:1008301. doi: 10.3389/fendo.2022.1008301. eCollection 2022.
CpG island methylator phenotype (CIMP), characterized by the concurrent and widespread hypermethylation of a cluster of CpGs, has been reported to play an important role in carcinogenesis. Limited studies have explored the role of CIMP in papillary thyroid carcinomas (PTCs). Here, in genome-wide DNA methylation analysis of 350 primary PTCs from the Cancer Genome Atlas database that were assessed using the Illumina HumanMethylation450K platform, our study helps to identify two subtypes displayed markedly distinct DNA methylation levels, termed CIMP (high levels of DNA methylation) and nCIMP subgroup (low levels of DNA methylation). Interestingly, PTCs with CIMP tend to have a higher degree of malignancy, since this subtype was tightly associated with older age, advanced pathological stage, and lymph node metastasis (all < 0.05). Differential methylation analysis showed a broad methylation gain in CIMP and subsequent generalized gene set testing analysis based on the significantly methylated probes in CIMP showed remarkable enrichment in epithelial mesenchymal transition and angiogenesis hallmark pathways, confirming that the CIMP phenotype may promote the tumor progression from another perspective. Analysis of tumor microenvironment showed that CIMP PTCs are in an immune-depletion status, which may affect the effectiveness of immunotherapy. Genetically, the significantly higher tumor mutation burden and copy number alteration both at the genome and focal level confirmed the genomic heterogeneity and chromosomal instability of CIMP. tumor Corresponding to the above findings, PTC patients with CIMP showed remarkable poor clinical outcome as compared to nCIMP regarding overall survival and progression-free survival. More importantly, CIMP was associated with worse survival independent of known prognostic factors.
CpG 岛甲基化表型（CIMP）的特征是一组 CpG 同时广泛过度甲基化，已被报道在肿瘤发生中起重要作用。有限的研究探索了 CIMP 在甲状腺乳头状癌（PTC）中的作用。在这里，我们通过对癌症基因组图谱数据库中 350 例原发性 PTC 的全基因组 DNA 甲基化分析，使用 Illumina HumanMethylation450K 平台进行评估，我们的研究有助于确定两种亚型，表现出明显不同的 DNA 甲基化水平，分别称为 CIMP（高水平的 DNA 甲基化）和 nCIMP 亚组（低水平的 DNA 甲基化）。有趣的是，具有 CIMP 的 PTC 往往具有更高的恶性程度，因为这种亚型与年龄较大、病理分期较晚和淋巴结转移密切相关（均<0.05）。差异甲基化分析显示 CIMP 中广泛的甲基化增益，随后基于 CIMP 中显著甲基化探针的广义基因集测试分析显示上皮间质转化和血管生成特征途径的显著富集，证实 CIMP 表型可能从另一个角度促进肿瘤进展。肿瘤微环境分析显示 CIMP PTC 处于免疫耗竭状态，这可能影响免疫治疗的效果。从遗传上看，基因组和局灶水平的显著更高的肿瘤突变负担和拷贝数改变都证实了 CIMP 的基因组异质性和染色体不稳定性。与上述发现相对应的是，与 nCIMP 相比，CIMP 患者的总生存率和无进展生存率明显较差。更重要的是，CIMP 与已知预后因素无关，与生存不良独立相关。
