Identifying Explainable Machine Learning Models and a Novel SFRP2+ Fibroblast Signature as Predictors for Precision Medicine in Ovarian Cancer

Ovarian cancer (OC) is a type of malignant tumor with a consistently high mortality rate. The diagnosis of early-stage OC and identification of functional subsets in the tumor microenvironment are essential to the development of patient management strategies. However, the development of robust models remains unsatisfactory. We aimed to utilize artificial intelligence and single-cell analysis to address this issue. Two independent datasets were screened from the Gene Expression Omnibus (GEO) database and processed to obtain overlapping differentially expressed genes (DEGs) in stage II-IV vs. stage I diseases. Three explainable machine learning algorithms were integrated to construct models that could determine the tumor stage and extract important characteristic genes as diagnostic biomarkers. Correlations between cancer-associated fibroblast (CAF) infiltration and characteristic gene expression were analyzed using TIMER2.0 and their relationship with survival rates was comprehensively explored via the Kaplan-Meier plotter (KM-plotter) online database. The specific expression of characteristic genes in fibroblast subsets was investigated through single-cell analysis. A novel fibroblast subset signature was explored to predict immune checkpoint inhibitor (ICI) response and oncogene mutation through Tumor Immune Dysfunction and Exclusion (TIDE) and artificial neural network algorithms, respectively. We found that Support Vector Machine-Shapley Additive Explanations (SVM-SHAP), Extreme Gradient Boosting (XGBoost), and Random Forest (RF) successfully diagnosed early-stage OC (stage I). The area under the receiver operating characteristic curves (AUCs) of these models exceeded 0.990. Their overlapping characteristic gene, secreted frizzled-related protein 2 (SFRP2), was a risk factor that affected the overall survival of OC patients with stage II-IV disease (log-rank test: p < 0.01) and was specifically expressed in a fibroblast subset. Finally, the SFRP2(+) fibroblast signature served as a novel predictor in evaluating ICI response and exploring pan-cancer tumor protein P53 (TP53) mutation (AUC = 0.853, 95% confidence interval [CI]: 0.829-0.877). In conclusion, the models based on SVM-SHAP, XGBoost, and RF enabled the early detection of OC for clinical decision making, and SFRP2(+) fibroblast signature used in diagnostic models can inform OC treatment selection and offer pan-cancer TP53 mutation detection.

Automated summary

This study developed models using artificial intelligence and single-cell analysis for early detection of ovarian cancer and extraction of important characteristic genes as diagnostic biomarkers. The expression of characteristic genes was associated with cancer-associated fibroblast infiltration and patient survival rates. Additionally, a novel fibroblast subset signature was explored to evaluate immune checkpoint inhibitor response and tumor protein P53 mutation.