POSTN/TGFBI-associated stromal signature predicts poor prognosis in serous epithelial ovarian cancer

- Two distinct molecular subgroups of high grade serous ovarian cancer were identified.
- Samples clustering with POSTN/TGFBI have significantly poorer overall survival than those clustering with ESR1/WT1 (30 mos vs 49 mos).
- Specific differentially expressed genes between these two subgroups provide potential therapeutic targets.

ObjectiveTo identify molecular prognosticators and therapeutic targets for high-grade serous epithelial ovarian cancers (EOCs) using genetic analyses driven by biologic features of EOC pathogenesis.MethodsOvarian tissue samples (n = 172; 122 serous EOCs, 30 other EOCs, 20 normal/benign) collected prospectively from sequential patients undergoing gynecologic surgery were analyzed using RNA expression microarrays. Samples were classified based on expression of genes with potential relevance in ovarian cancer. Gene sets were defined using Rosetta Similarity Search Tool (ROAST) and analysis of variance (ANOVA). Gene copy number variations were identified by array comparative genomic hybridization.ResultsNo distinct subgroups of EOC could be identified by unsupervised clustering, however, analyses based on genes correlated with periostin (POSTN) and estrogen receptor-alpha (ESR1) yielded distinct subgroups. When 95 high-grade serous EOCs were grouped by genes based on ANOVA comparing ESR1/WT1 and POSTN/TGFBI samples, overall survival (OS) was significantly shorter for 43 patients with tumors expressing genes associated with POSTN/TGFBI compared to 52 patients with tumors expressing genes associated with ESR1/WT1 (median 30 versus 49 months, respectively; P = 0.022). Several targets with therapeutic potential were identified within each subgroup. BRCA germline mutations were more frequent in the ESR1/WT1 subgroup. Proliferation-associated genes and TP53 status (mutated or wild-type) did not correlate with survival. Findings were validated using independent ovarian cancer datasets.ConclusionsTwo distinct molecular subgroups of high-grade serous EOCs based on POSTN/TGFBI and ESR1/WT1 expressions were identified with significantly different OS. Specific differentially expressed genes between these subgroups provide potential prognostic and therapeutic targets.