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

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.

Methylation in HOX Clusters and Its Applications in Cancer Therapy

“…The methylation profile of HOXA9 has also been proposed as a reliable biomarker to identify resistance to cisplatin-based therapy in bladder cancer [34], and as a tool for testicular germ cell tumors subtyping [100]. In addition, the methylation status of HOXA9 was considered relevant for subtyping lung cancer using liquid biopsies [110] or for its early detection in circulating cell-free DNA [58]. HOXA9 hypermethylation was also found to be a tool to identify advanced neck squamous cell carcinomas favoring tumor progression and metastasis [57], predict survival in breast cancer patients, together with HOXA10 hypermethylation [111], and detect early onset of endometrial cancer [58].…”

“…The DNA methylation level of HOXD10 is part of a profile that is significantly correlated with a higher aggressiveness of early-onset endometrial cancer [58]. In addition, it is a recognizable marker in papillary thyroid cancer patients, particularly among BRAFV600E mutation carriers [104].…”

“…In addition, it is a recognizable marker in papillary thyroid cancer patients, particularly among BRAFV600E mutation carriers [104]. It has also been suggested that HOXD10 hypermethylation detection in the plasma, in combination with other genes, may be a useful biomarker for the early detection of gastric cancer and pre-cancerous lesions [58], and to distinguish lung cancer, pulmonary fibrosis and chronic obstructive lung disease [82]. The downstream impact of these epigenetic aberrations is still not fully characterized.…”

Cooperative participation of epigenomic and genomic alterations in the clinicopathological diversity of gastric adenocarcinomas: significance of cell adhesion and epithelial–mesenchymal transition-related signaling pathways

“…Hierarchical clustering based on genome-wide DNA methylation profiles has allowed patients with cancers of various organs to be stratified into subclasses associated with distinct clinicopathological features ( 34 ), probably because DNA methylation alterations arise even from the precancerous stages and are then stably preserved on DNA double strands by covalent bonds due to maintenance methylation mechanisms attributable to DNA methyltransferase DNMT1 ( 35 ). For example, in relation to treatment strategy, our previous studies have shown that epigenomic clustering of renal cell carcinomas of the kidney ( 10 ) and young-onset endometrial cancers of the uterine corpus ( 36 ) are closely associated with amenability to Aurora kinase inhibitors and fertility preservation therapy, respectively. In terms of prognostic impact, such clustering of lung adenocarcinomas was shown to be associated with history of smoking and chronic obstructive pulmonary disease and poor prognosis ( 11 ).…”

miR‑429 inhibits osteosarcoma progression by targeting HOXA9 through suppressing Wnt/β‑catenin signaling pathway

“…For instance, increasing expression of HOXA9 inhibited lung cancer cell invasion and migration (19). Makabe et al (20) found that HOXA9 was involved in endometrial carcinogenesis. Furthermore, HOXA9 was reported to promote leukemogenesis (21).…”