Characterization of the CpG island methylator phenotype subclass in papillary thyroid carcinoma

Abstract

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 P < 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.

CTC, ctDNA, and Exosome in Thyroid Cancers: A Review

“…The methylation of ctDNA correlated with tumor-specific alterations and is considered a promising biomarker in several cancers. Currently, in several research studies, the hypermethylation of cytosine-phosphate-uracil (CpG) island promoters has been considered to be a crucial component in the inactivation of tumor suppressor genes in thyroid cancer [ 97 , 98 ]. In Khatami’s study [ 99 ], in PTC patients, the methylation of two O6-methylguanine-DNA methyltransferase (MGMT) promoter areas (c) and (d) was considerably higher than in goiter controls, suggesting that MGMT may be associated with PTC.…”

Liquid Biopsy as a Method for Minimally Invasive Diagnosis of Thyroid Cancer

“…Клетки ФК часто содержат мутации генов RAS, DICER1, PTEN, pTERT, EIF1AX, TP53, PIK3CA, EZH1, IDH1 и SPOP и парное слияние генов PAX8+PPARG [34,42]. Кроме того, известно, что при дифференцированном раке ЩЖ наблюдается изменение метилирования ряда CpG-островков по сравнению с нормальной тканью [43,44]. Так, для ПК ЩЖ в первую очередь характерно наличие участков гиперметилирования генов MIG-6, SLC26A4, COL4A2, DACT2, RASSF1 и гипометилирования гена KLK10, а ФК содержит большое количество участков гиперметилирования в генах THRβ, DLEC1, RASSF1, ZIC1, p16 INK4A [45][46][47][48][49].…”

Association of DNA Promoter Methylation and BRAF Mutation in Thyroid Cancer

“…DNA methylation, the most widely studied epigenetic mechanism, varies in different cancers, and is notably altered in thyroid cancer [ 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 ]. Now, the role of DNA methylation in cancer is being widely studied to determine markers that might guide treatment.…”

“…Now, the role of DNA methylation in cancer is being widely studied to determine markers that might guide treatment. Methylation markers may also detect different subtypes of thyroid cancer and augment early detection efforts [ 26 ]. The cancer genome is typically characterized by global hypomethylation concomitant with hypermethylation of the CpG island of the promoter regions associated with different cellular regulatory functions [ 33 ].…”

“…The BRAF V600E mutation is common in thyroid cancer [ 13 , 15 , 16 , 18 , 22 , 23 , 25 ], as is DNA methylation [ 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 ]. However, the interaction or association between them is not well-studied.…”