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Integrative analysis of genomic and epigenetic regulation of endometrial cancer.

ABSTRACT: Endometrial carcinomas (EC) are characterized by high DNA copy numbers and DNA methylation aberrations. In this study, we sought to comprehensively explore the effect of these two factors on development and progression of EC by analyzing integrated genomic and epigenetic analysis to. We found high DNA copy number and DNA methylation abnormalities in EC, with 6308 copy-number variation genes (CNV-G) and 4376 methylation genes (MET-G). We used these CNV-G and MET-G to subcategorize the samples for prognostic analysis, and identified three molecular subtypes (iC1, iC2, iC3). Moreover, the subtypes exhibited different tumor immune microenvironment characteristics. A further analysis of their molecular characteristics revealed three potential prognostic markers (KIAA1324, nonexpresser of pathogenesis-related genes1 (NPR1) and idiopathic hypogonadotropic hypogonadism (IHH)). Notably, all three markers showed distinct CNV, DNA methylation, and gene expression profiles. Analysis of mutations among the three subtypes revealed that iC2 had fewer mutations than the other subtypes. Conversely, iC2 showed significantly higher CNV levels than other subtypes. This comprehensive analysis of genomic and epigenetic profiles identified three prognostic markers, therefore, provides new insights into the multi-layered pathology of EC. These can be utilized for accurate treatment of EC patients.

SUBMITTER: Zhong Q

PROVIDER: S-EPMC7288931 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Integrative analysis of genomic and epigenetic regulation of endometrial cancer.

Zhong Qihang Q Fan Junpeng J Chu Honglei H Pang Mujia M Li Junsheng J Fan Yong Y Liu Ping P Wu Congying C Qiao Jie J Li Rong R Hang Jing J

Aging 20200515 10

Endometrial carcinomas (EC) are characterized by high DNA copy numbers and DNA methylation aberrations. In this study, we sought to comprehensively explore the effect of these two factors on development and progression of EC by analyzing integrated genomic and epigenetic analysis to. We found high DNA copy number and DNA methylation abnormalities in EC, with 6308 copy-number variation genes (CNV-G) and 4376 methylation genes (MET-G). We used these CNV-G and MET-G to subcategorize the samples for ...[more]

PMID: 32412912

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Project description:BACKGROUND:L1CAM was originally identified as an adhesion molecule involved in neural development. In many human carcinomas L1CAM is over-expressed and is associated with a bad prognosis. We previously reported that L1CAM was absent in the vast majority of endometrioid endometrial carcinomas (ECs) (type 1) but was strongly expressed in the more aggressive serous and clear-cell ECs (termed type 2). The differential regulation of L1CAM in ECs is not well understood. Recent evidence suggests that it can be regulated by epigenetic mechanisms. Here we investigated the role of DNA-methylation of the L1CAM promoter for expression. We also studied the relationship to cancer testis (CT-X) antigens that co-localize with L1CAM on chromosome Xq28, a region that is often activated in human tumors. METHODS:We used EC cell lines and primary tumor tissues for our analysis. For expression analysis we employed RT-PCR and Western blotting. DNA-Methylation of the L1CAM promoter was determined after bisulfite conversation and DNA sequencing. Tumor tissues were examined by immunohistochemical (IHC) staining. RESULTS:We demonstrate that the treatment of L1CAM low/negative expressing EC cell lines with 5'-Azacytidine (5-AzaC) or knock-down of DNMT1 (DNA methyltransferase 1) as well as the HDAC (histone deacetylase) inhibitor Trichostatin A (TSA) up-regulated L1CAM at the mRNA and protein level. The L1CAM gene has two promoter regions with two distinct CpG islands. We observed that the expression of L1CAM correlated with hypermethylation in promoter 1 and 5-AzaC treatment affected the DNA-methylation pattern in this region. The CT-X antigens NY-ESO-1, MAGE-A3 and MAGE-A4 were also strongly up-regulated by 5-AzaC or knock-down of DNMT1 but did not respond to treatment with TSA. Primary EC tumor tissues showed a variable methylation pattern of the L1CAM promoter. No striking differences in promoter methylation were observed between tumor areas with L1CAM expression and those without expression. CONCLUSIONS:L1CAM expression correlated with methylation of the L1CAM promoter in EC cell lines. In negative cell lines L1CAM expression is up-regulated by epigenetic mechanism. Although genes localized on Xq28 are often re-expressed by human tumors, L1CAM and CT-X antigens show distinct regulation in response to HADC inhibitors and 5-AzaC.

Dataset Information

Integrative analysis of genomic and epigenetic regulation of endometrial cancer.

Publications

Integrative analysis of genomic and epigenetic regulation of endometrial cancer.

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