Prognostically relevant gene signatures of high-grade serous ovarian carcinoma

Abstract

Because of the high risk of recurrence in high-grade serous ovarian carcinoma (HGS-OvCa), the development of outcome predictors could be valuable for patient stratification. Using the catalog of The Cancer Genome Atlas (TCGA), we developed subtype and survival gene expression signatures, which, when combined, provide a prognostic model of HGS-OvCa classification, named "Classification of Ovarian Cancer" (CLOVAR). We validated CLOVAR on an independent dataset consisting of 879 HGS-OvCa expression profiles. The worst outcome group, accounting for 23% of all cases, was associated with a median survival of 23 months and a platinum resistance rate of 63%, versus a median survival of 46 months and platinum resistance rate of 23% in other cases. Associating the outcome prediction model with BRCA1/BRCA2 mutation status, residual disease after surgery, and disease stage further optimized outcome classification. Ovarian cancer is a disease in urgent need of more effective therapies. The spectrum of outcomes observed here and their association with CLOVAR signatures suggests variations in underlying tumor biology. Prospective validation of the CLOVAR model in the context of additional prognostic variables may provide a rationale for optimal combination of patient and treatment regimens.

Figure 1. HGS-OvCa signature ssGSEA scores. ssGSEA scores for 489 HGS-OvCa tumor samples were generated using 4 previously described gene expression signatures (20): differentiated (D), immunoreactive (I), mesenchymal (M), and proliferative (P).

(A) Binary scores indicating whether a tumor sample activates the gene signature. Each column represents 1 sample; each row represents 1 gene signature. Red, activated; black, not activated. (B) Raw gene set activation scores. Each column represents 1 sample; each row represents 1 gene signature. (C) Scatter plots and r² values (numbers within plots) for all gene set combinations.

Figure 2. Survival per CLOVAR subtype, CLOVAR survival class, and double classifiers.

Kaplan Meier curves for CLOVAR survival class (A), survival per CLOVAR subtype (B), and double classification of samples by both CLOVAR subtype and CLOVAR survival signature (C). Data represent survival capped at 60 months for 879 samples in the validation set. (D) A further significant difference in survival was observed between optimally and suboptimally debulked CLOVAR Mesenchymal/CLOVAR poor prognosis patients.

Figure 3. Survival analysis of multiple covariate outcome predictions.

A multiple covariate proportional hazards model was trained using (A) only CLOVAR survival and CLOVAR subtype signatures; (B) CLOVAR survival and CLOVAR subtype signatures, stage, grade, age, and residual disease; or (C) CLOVAR survival and CLOVAR subtype signatures, stage, grade, age, residual disease, and BRCA1/BRCA2 germline mutations. Models were trained on a training dataset (TCGA samples; n = 273) and tested on the validation set (n = 83), including all samples with nonmissing data on all variables. The difference in outcome of the 3 predicted groups was tested using Kaplan-Meier survival analysis.