Tube to Tumour: an integrative epigenomic analysis of DNA methylation in high-grade serous ovarian cancer and precursor serous tubal intraepithelial carcinoma

Abstract

Serous tubal intraepithelial carcinoma (STIC) is a known precursor of high-grade serous ovarian cancer (HGSOC). Yet, molecular events driving progression from STIC to HGSOC remain poorly defined. Aberrant DNA methylation is a hallmark of cancer, yet its role in early HGSOC remains unclear. We performed a comprehensive meta-analysis of publicly available Illumina Infinium DNA methylation EPIC array datasets assessing 255 samples comprising STIC, HGSOC, and histologically normal fallopian tube tissues. We mapped DNA methylation alterations during early tumorigenesis, identified conserved methylation patterns across STIC and HGSOC, and assessed RNA-sequencing data to define transcriptional consequences within genomic and epigenomic landscapes. STIC and HGSOC exhibited widespread DNA hypomethylation relative to normal tissue, accompanied by focal hypermethylation in CpG islands and 5' regulatory regions. DNA Hypomethylation intensifies during progression from STIC to HGSOC, particularly in cis-regulatory enhancer domains and intergenic regions. We identified 11,660 CpG sites and 447 genomic regions with conserved DNA methylation patterns across STIC and HGSOC. Within these, 70 genes showed coordinated DNA methylation and expression changes, including TRIM15, NKAPL, and RIPPLY3. These findings reveal that epigenetic remodelling occurs in STIC lesions, prior to malignant transformation. DNA methylation alterations at regulatory regions may drive invasion and offer novel avenues for early detection and targeted intervention.