Mutatioal profiling from next generation sequencing of longitudinal biopsies of epithelial ovarian cancer (EOC)

Stage III/IV epithelial ovarian cancer (EOC) is a systemic disease. It is not yet defined the clonal relationship among different tumor lesions at time of diagnosis (spatial heterogeneity) and how tumor clonal architecture evolves over time (temporal heterogeneity). This knowledge is fundamental for developing new target-based strategies, as biomarker selected for therapeutic intervention must be independent of spatial and temporal heterogeneity. By taking advantage of unique cohort of 19 patients with stage III/IV EOC and for whom multiple biopsies were available at time of primary surgery, when tumor was naïve to chemotherapy, and after different lines of chemotherapy, we inferred by targeted NGS technology the issue of tumor spatial and temporal heterogeneity. Matched tumor lesions growing in the ovary or in other anatomical sites show a completely different mutational landscape, with branched tumor evolution. Mutations in ATM, ATR and TGFB3 genes were shared across all lesions, while BRCA1 and BRCA2 were more frequently mutated in synchronous lesions. Relapsed disease seems to originate from resistant clones originally present at time of primary surgery, rather than de novo acquisition. EOC continue to evolve, and more detailed mapping of genetic lesions is required for improving therapeutic strategies.