Ovarian cancer has a poor prognosis and is difficult to detect in early stages. Therefore, developing new diagnostic markers for early-stage ovarian cancer is critical. Here, we developed a diagnostic marker for early-stage ovarian cancer on the basis of fatty acid metabolism characteristics of cancer cells. The expression of various fatty acid metabolizing enzymes such as stearoyl-CoA desaturase 1 (SCD1) was altered in early-stage ovarian cancer tissue compared with that in normal ovarian tissue. Changes in the expression of fatty acid metabolizing enzymes, particularly SCD1, in cancer tissues were found to alter concentrations of multiple free fatty acids (FFA) in serum. We were the first to show that fatty acid metabolic characteristics in tissues are related to the FFA composition of serum. Surprisingly, patients with stage I/II ovarian cancer also showed significant changes in serum levels of eight FFAs, which can be early diagnostic markers. Finally, using statistical analysis, an optimal early diagnostic model combining oleic and arachidic acid levels, fatty acids associated with SCD1, was established and confirmed to have higher diagnostic power than CA125, regardless of histology. Thus, our newly developed diagnostic model using serum FFAs may be a powerful tool for the noninvasive early detection of ovarian cancer. Significance: Measurement of serum FFA levels by changes in the expression of fatty acid metabolizing enzymes in tumor tissue would allow early detection of ovarian cancer. In particular, the SCD1-associated FFAs, oleic and arachidic acid, would be powerful new screening tools for early-stage ovarian cancer.

Persistent infections with two types of human papillomaviruses (HPV), HPV16 and HPV18, are the most common cause of cervical cancer (CC). Two viral early genes, E6 and E7, are associated with tumor development, and expressions of E6 and E7 are primarily regulated by a single viral promoter: P97 in HPV16 and P105 in HPV18. We previously demonstrated that the homeobox D9 (HOXD9) transcription factor is responsible for the malignancy of HPV16-positive CC cell lines via binding to the P97 promoter. Here, we investigated whether HOXD9 is also involved in the regulation of the P105 promoter using two HPV18-positive CC cell lines, SKG-I and HeLa. Following the HOXD9 knockdown, cell viability was significantly reduced, and E6 expression was suppressed and was accompanied by increased protein levels of P53, while mRNA levels of TP53 did not change. E7 expression was also downregulated and, while mRNA levels of RB1 and E2F were unchanged, mRNA levels of E2F-target genes, MCM2 and PCNA, were decreased, which indicates that the HOXD9 knockdown downregulates E7 expression, thus leading to an inactivation of E2F and the cell-cycle arrest. Chromatin immunoprecipitation and promoter reporter assays confirmed that HOXD9 is directly associated with the P105 promoter. Collectively, our results reveal that HOXD9 drives the HPV18 early promoter activity to promote proliferation and immortalization of the CC cells.

Chen G, et al. J Gynecol Oncol. 2022 Oct;34(1):e2. https://doi.org/10.3802/jgo.2023.34.e2

Background/Objectives: Endometrial cancer (EC) is the most prevalent gynecological malignancy in developed countries, yet no clinically validated noninvasive screening biomarker exists. Fatty acid metabolic reprogramming is a hallmark of cancer that produces measurable changes in systemic free fatty acid (FFA) profiles. We aimed to identify serum FFAs altered in EC and evaluate their potential as early diagnostic biomarkers. Methods: Gene expression of fatty acid metabolic enzymes in EC tissues was assessed using public databases. Serum levels of 19 FFAs were quantified by gas chromatography–mass spectrometry in 72 patients with EC and 84 healthy donors. A two-variable diagnostic model was constructed using logistic regression and validated in an independent dataset. Results: Multiple fatty acid metabolic enzymes involved in de novo synthesis were upregulated in EC tissues as early as stage I, while enzymes mediating fatty acid uptake and release were downregulated. Serum levels of palmitoleic acid, oleic acid and dihomo-γ-linolenic acid were significantly elevated, whereas arachidic acid and arachidonic acid were significantly decreased in patients with EC from stage I onward. A diagnostic model combining palmitoleic acid and arachidonic acid achieved an area under the receiver operating characteristic curve of 0.9674, with a sensitivity of 91.3% and specificity of 96.4% in the validation dataset, including for stage I disease, and was independent of body mass index, age, metastasis status, and family history. Conclusions: Serum FFA profiling represents a promising noninvasive strategy for early EC detection, with the potential to complement existing diagnostic methods.

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.

Gastric-type adenocarcinoma (GAS) of the cervix is usually diagnosed at advanced stages and has a poor prognosis due to resistance to standard therapies. Although immune checkpoint inhibitors have improved outcomes in cervical cancer, prognosis and treatment response are strongly influenced by the tumor immune microenvironment (TME). Histopathological assessment of GAS is challenging because it often arises in the upper cervix. This study aimed to predict the TME in GAS using MRI-based radiomics. We enrolled 16 patients with GAS treated at our institution. Tumor-infiltrating lymphocytes (TILs) were evaluated by immunohistochemistry, quantifying them with the Immunoscore. Fourteen patients with usual endocervical adenocarcinoma (UEA) served as controls. A total of 1,309 radiomic features were extracted from the primary tumor and peritumoral region on pre-treatment MRI images. After feature selection, clustering, and regression models were developed to predict the TME in GAS. GAS exhibited significantly lower T-cell infiltration than UEA, particularly in early-stage tumors. The clustering model achieved 87.5% accuracy in Immunoscore classification, and the regression model showed a strong correlation with observed TIL densities (r = 0.93, P < .001). These findings suggest that MRI-based radiomics may serve as a noninvasive biomarker for predicting the TME in GAS.