In women under 50 years of age, the combination of HE4 and CA125 where either was positive performed the best, improving sensitivity (100%, 95%CI 81.5–100) but at a cost to specificity (80.1%, 95%CI 76.7–83.1), which, in our cohort would lead to an additional 67 referrals for further evaluation, of which 2 (3%) would have ovarian cancer (1 in 34), compared to using CA125 alone. Here, WFDC2 is linked to ovarian cancer.