Genome-wide DNA methylation profile of early-onset endometrial cancer: Its correlation with genetic aberrations and comparison with late-onset endometrial cancer

Takeshi Makabe, Eri Arai, Takuro Hirano, Nanako Ito, Yukihiro Fukamachi, Yoriko Takahashi, Akira Hirasawa, Wataru Yamagami, Nobuyuki Susumu, Daisuke Aoki, Yae Kanai

Research output: Contribution to journalArticle

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Abstract

The present study was performed to clarify the significance of DNA methylation alterations during endometrial carcinogenesis. Genome-wide DNA methylation analysis and targeted sequencing of tumor-related genes were performed using the Infinium MethylationEPIC BeadChip and the Ion AmpliSeq Cancer Hotspot Panel v2, respectively, for 31 samples of normal control endometrial tissue from patients without endometrial cancer and 81 samples of endometrial cancer tissue. Principal component analysis revealed that tumor samples had a DNA methylation profile distinct from that of control samples. Gene Ontology enrichment analysis revealed significant differences of DNA methylation at 1034 CpG sites between early-onset endometrioid endometrial cancer (EE) tissue (patients aged ≤40 years) and late-onset endometrioid endometrial cancer (LE) tissue, which were accumulated among 'transcriptional factors'. Mutations of the CTNNB1 gene or DNA methylation alterations of genes participating in Wnt signaling were frequent in EEs, whereas genetic and epigenetic alterations of fibroblast growth factor signaling genes were observed in LEs. Unsupervised hierarchical clustering grouped EE samples in Cluster EA (n = 22) and samples in Cluster EB (n = 12). Clinicopathologically less aggressive tumors tended to be accumulated in Cluster EB, and DNA methylation levels of 18 genes including HOXA9, HOXD10 and SOX11 were associated with differences in such aggressiveness between the two clusters. We identified 11 marker CpG sites that discriminated EB samples from EA samples with 100% sensitivity and specificity. These data indicate that genetically and epigenetically different pathways may participate in the development of EEs and LEs, and that DNA methylation profiling may help predict tumors that are less aggressive and amenable to fertility preservation treatment.

Original languageEnglish
Pages (from-to)611-623
Number of pages13
JournalCarcinogenesis
Volume40
Issue number5
DOIs
Publication statusPublished - 2019 Jul 4

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DNA Methylation
Endometrial Neoplasms
Genome
Genes
Neoplasms
Fertility Preservation
Gene Ontology
DNA Fingerprinting
Fibroblast Growth Factors
Principal Component Analysis
Epigenomics
Cluster Analysis
Carcinogenesis
Ions
Sensitivity and Specificity
Mutation

ASJC Scopus subject areas

  • Cancer Research

Cite this

Genome-wide DNA methylation profile of early-onset endometrial cancer : Its correlation with genetic aberrations and comparison with late-onset endometrial cancer. / Makabe, Takeshi; Arai, Eri; Hirano, Takuro; Ito, Nanako; Fukamachi, Yukihiro; Takahashi, Yoriko; Hirasawa, Akira; Yamagami, Wataru; Susumu, Nobuyuki; Aoki, Daisuke; Kanai, Yae.

In: Carcinogenesis, Vol. 40, No. 5, 04.07.2019, p. 611-623.

Research output: Contribution to journalArticle

Makabe, Takeshi ; Arai, Eri ; Hirano, Takuro ; Ito, Nanako ; Fukamachi, Yukihiro ; Takahashi, Yoriko ; Hirasawa, Akira ; Yamagami, Wataru ; Susumu, Nobuyuki ; Aoki, Daisuke ; Kanai, Yae. / Genome-wide DNA methylation profile of early-onset endometrial cancer : Its correlation with genetic aberrations and comparison with late-onset endometrial cancer. In: Carcinogenesis. 2019 ; Vol. 40, No. 5. pp. 611-623.
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AU - Takahashi, Yoriko

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