Serum Free Fatty Acid-Based Diagnostic Index for Cervical Cancer Including High-Risk HPV-Negative Cases: An Independent Validation Study.

Background/Objectives: Cervical cancer (CC) is usually caused by high-risk human papillomavirus (hrHPV); however, some hrHPV-negative cases are undetectable by current screening programs. We evaluated a previously established diagnostic model based on serum free fatty acids (FFAs) in an independent cohort including hrHPV-negative CC. Methods: We analyzed serum FFAs from 101 patients with CC (16 hrHPV-negative), 60 healthy donors, and 16 patients with benign gynecological diseases, none of whom were included in the previous study, and gene expression levels of fatty acid metabolism-related enzymes in 64 surgical CC and five normal cervix samples. Results: Levels of nine FFAs differed between CC and the non-cancer groups but not between hrHPV-negative and hrHPV-positive CC. Gene expression levels of acetyl-CoA carboxylase 1, fatty acid synthase, stearoyl-CoA desaturase 1, and monoacylglycerol lipase were increased in CC compared with normal tissues, with no significant differences between hrHPV-negative and hrHPV-positive CC. The previous model (diagnostic index = -5.631 + 0.030 × (stearic acid) + 9.188 × (dihomo-γ-linolenic acid)) distinguished CC from the non-cancer groups (area under the curve, 0.969). At the pre-specified cut-off value, sensitivity was 97.0% (hrHPV-negative CC, 93.8%) and specificity in healthy donors was 58.3%; at the cut-off value derived in this cohort, these were 82.2% (93.8%) and 98.3%, respectively. In hrHPV-negative CC, the positivity rate exceeded those of squamous cell carcinoma antigen, carcinoembryonic antigen, and CA125. Conclusions: The serum-FFA-based diagnostic model detected CC, including hrHPV-negative cases, in an independent cohort. With calibration of the cut-off value, this approach may complement existing HPV-based testing.