// Lara Paracchini 1, * , Laura Mannarino 1, * , Ilaria Craparotta 1 , Chiara Romualdi 2 , Robert Fruscio 3 , Tommaso Grassi 3 , Vittoria Fotia 4 , Giulia Caratti 1 , Patrizia Perego 5 , Enrica Calura 2 , Luca Clivio 1 , Maurizio D’Incalci 1 , Luca Beltrame 1, § , Sergio Marchini 1, § 1 Department of Oncology, IRCCS Istituto di Ricerche Farmacologiche “Mario Negri”, Milano, Italy 2 Department of Biology, University of Padova, Padova, Italy 3 Clinic of Obstetrics and Gynaecology, University of Milano-Bicocca, San Gerardo Hospital, Monza, Italy 4 PhD program in Experimental Medicine, University of Pavia, Italy 5 Pathology Unit University of Milan-Bicocca, San Gerardo Hospital, Monza, Italy * both are first authors § both are last co-authors Correspondence to: Maurizio D’Incalci, email: email@example.com Keywords: ovarian cancer, temporal heterogeneity, spatial heterogeneity, targeted next generation sequencing, drug resistance Received: March 01, 2016     Accepted: May 23, 2016     Published: July 09, 2016 ABSTRACT Stage III/IV epithelial ovarian cancer (EOC) is a systemic disease. The clonal relationship among different tumor lesions at diagnosis (spatial heterogeneity) and how tumor clonal architecture evolves over time (temporal heterogeneity) have not yet been defined. Such knowledge would help to develop new target-based strategies, as biomarkers which can adjudge the success of therapeutic intervention should be independent of spatial and temporal heterogeneity. The work described in this paper addresses spatial and temporal heterogeneity in a cohort of 71 tumor biopsies using targeted NGS technology. These samples were taken from twelve high grade serous (HGS) and seven non HSG-EOC, both at the time of primary surgery when the tumor was naïve to chemotherapy and after chemotherapy. Matched tumor lesions growing in the ovary or at other anatomical sites show very different mutational landscapes with branched tumor evolution. Mutations in ATM, ATR, TGFB3, VCAM1 and COL3A1 genes were shared across all lesions. BRCA1 and BRCA2 genes were frequently mutated in synchronous lesions of non HGS-EOC. Relapsed disease seems to originate from resistant clones originally present at the time of primary surgery rather than from resistance acquired de novo during platinum based therapy. Overall the work suggests that EOC continues to evolve. More detailed mapping of genetic lesions is necessary to improve therapeutic strategies.
Paracchini, L., Mannarino, L., Craparotta, I., Romualdi, C., Fruscio, R., Grassi, T., … Marchini, S. (2016). Regional and temporal heterogeneity of epithelial ovarian cancer tumor biopsies: implications for therapeutic strategies. Oncotarget. https://doi.org/10.18632/oncotarget.10505