Despite a myriad of attempts in the last three decades to diagnose ovarian cancer (OC) and breast cancer (BC) earlier, this clinical aim remains a significant challenge. Aberrant methylation patterns of linked CpGs analyzed in DNA fragments shed by cancers into the bloodstream (i.e. cell-free DNA) can provide highly specific signals indicating cancer presence. We analyzed cancerous and non-cancerous tissues using a methylation array or reduced representation bisulfite sequencing to discover the most specific OC and BC methylation patterns. A DNA-methylation-serum-marker panel was developed using targeted ultra-high coverage bisulfite sequencing in 151 women and validated in 250 women with various conditions, particularly those associated with high CA125 levels (endometriosis and other benign pelvic masses), serial samples from 25 patients undergoing neoadjuvant chemotherapy and a nested case control study of 172 UKCTOCS control arm participants which included serum samples up to two years prior to OC diagnosis.