Large-scale integrated analysis of ovarian cancer tumors and cell lines identifies an individualized gene expression signature for predicting response to platinum-based chemotherapy

Abstract

Heterogeneity in chemotherapeutic response is directly associated with prognosis and disease recurrence in patients with ovarian cancer (OvCa). Despite the significant clinical need, a credible gene signature for predicting response to platinum-based chemotherapy and for guiding the selection of personalized chemotherapy regimens has not yet been identified. The present study used an integrated approach involving both OvCa tumors and cell lines to identify an individualized gene expression signature, denoted as IndividCRS, consisting of 16 robust chemotherapy-responsive genes for predicting intrinsic or acquired chemotherapy response in the meta-discovery dataset. The robust performance of this signature was subsequently validated in 25 independent tumor datasets comprising 2215 patients and one independent cell line dataset, across different technical platforms. The IndividCRS was significantly correlated with the response to platinum therapy and predicted the improved outcome. Moreover, the IndividCRS correlated with homologous recombination deficiency (HRD) and was also capable of discriminating HR-deficient tumors with or without platinum-sensitivity for guiding HRD-targeted clinical trials. Our results reveal the universality and simplicity of the IndividCRS as a promising individualized genomic tool to rapidly monitor response to chemotherapy and predict the outcome of patients with OvCa.

Fig. 1. Development of a 16-gene signature.

a Forest plot illustrating the Hazard ratios (HRs) of fixed-effect meta-analysis summary result for each of the 16 chemotherapy-responsive genes. The HR shown for each gene is leveraged from univariate and multivariate Cox-PH analysis across 21 ovarian cancer cohorts. Colored rectangles on the left indicate the logFC of gene expression comparing chemo-sensitive to chemo-resistant tumors. b Kaplan–Meier curves of OS for patients divided by the IndividCRS in the Patch and TCGA datasets. Significance was determined using the log-rank test. c Distribution of the IndividCRS and expression heatmap of 16 chemotherapy-responsive genes in the Patch and TCGA datasets. HR, hazard ratio; OS, overall survival; IndividCRS, individual chemotherapeutic response scores; TCGA, The Cancer Genome Atlas Network; CR: Complete response; PR: partial response; PD: progression disease; SD: stable disease

Fig. 2. Association between the IndividCRS and chemotherapy response in four independent datasets.

Violin Plot illustrating the distribution and probability density of the IndividCRS, and the distribution of the IndividCRS and expression heatmap of 16 chemotherapy-responsive genes in the a GDSC dataset, b GSE3149 dataset, c GSE51373 dataset, and d GSE23554 dataset. Patients with chemotherapy sensitivity exhibited higher IndividCRS than those with chemotherapy resistance. Significance was determined using an unpaired t-test. IndividCRS, individual chemotherapeutic response scores

Fig. 3. Association between the IndividCRS and HRD.

a Pairwise comparison of the IndividCRS between HR-intact tumors and HR-defective tumors including those with a BRCA mutation, BRCA methylation, EMSY amplification, and defects in PTEN and FA genes. Significance was determined using the Wilcoxon rank-sum test. b Kaplan–Meier curves of OS for high IndividCRS HR-defective tumors and low IndividCRS HR-defective tumors versus HR-intact tumors. The high IndividCRS group of HR-defective tumors showed significantly improved OS, whereas low IndividCRS group of HR-defective tumors showed no significant difference in OS compared with HR-intact tumors. Significance was determined using the log-rank test. c Kaplan–Meier curves of OS for high IndividCRS BRCA-deficient tumors and low IndividCRS BRCA-deficient tumors versus BRCA1/2-intact tumors. The high IndividCRS group of BRCA-deficient tumors showed significantly improved OS, whereas low IndividCRS group of BRCA-deficient tumors showed no significant difference in OS compared with BRCA1/2-intact tumors. Significance was determined using the log-rank test. IndividCRS, individual chemotherapeutic response scores; HRD, homologous recombination deficiency; PTEN, phosphatase and tensin homolog; FA, Fanconi anemia; OS, overall survival

Fig. 4. Association between the IndividCRS and enhanced resistance in samples treated with multiple cycles of chemotherapy.

a Pairwise comparison of the IndividCRS in 46 cell lines before and after 48 h treatment with cisplatin. Significance was determined using a paired t-test. b Violin Plot illustrating the distribution and probability density of the IndividCRS in samples before and after five rounds of cisplatin treatment. Significance was determined using a paired t-test. c Pairwise comparison of the IndividCRS in patients before and after three cycles of carboplatin treatment. Significance was determined using a paired t-test. d Pairwise comparison of the IndividCRS in samples before and after three cycles of paclitaxel treatment. Significance was determined using paired t-test. e Pairwise comparison of the IndividCRS in samples post- and pre-chemotherapy. Significance was determined using an unpaired t-test. IndividCRS, individual chemotherapeutic response scores

Fig. 5. Association between platinum resistance and EMT.

a Pairwise comparison of the IndividCRS in four OvCa subtypes, including immunoreactive, differentiated, proliferative and mesenchymal. Significance was determined using the Wilcoxon rank-sum test. b Bubble plot showing the correlation between the IndividCRS and EMT score, ZEB1 and Ki67 across 19 patient datasets. The size of the circles proportional to the significance of the correlation and the color of the border indicates Pearson correlation coefficients. Correlation of the IndividCRS with EMT score in the c TCGA dataset and d Patch dataset, and e ZEB1 in the Patch dataset. The orange line represents the line of linear regression through the data points. EMT, epithelial-mesenchymal transition; IndividCRS, individual chemotherapeutic response scores; OvCa, ovarian cancer; ZEB1, zinc finger E-box binding homeobox 1

Fig. 6. Prognostic value of the IndividCRS in predicting clinical outcome.

a, b Kaplan–Meier curves of OS for patients in low IndividCRS and high IndividCRS subgroups. Significance was determined using the log-rank test. b Forest plot illustrating the HRs of survival analyses of low-IndividCRS group versus high-IndividCRS in 21 patient datasets. Significance was determined using the Cox proportional hazards model. The red diamond indicates the fixed-effects meta-analysis summary of HRs over 21 datasets. c Multivariable analyses using Cox proportional hazards models were performed for all patients in 21 datasets. IndividCRS, individual chemotherapeutic response scores; OS, overall survival; HR, hazard ratio, CI, confidence interval