Oncotarget

Research Papers:

Regional and temporal heterogeneity of epithelial ovarian cancer tumor biopsies: implications for therapeutic strategies

Lara Paracchini, Laura Mannarino, Ilaria Craparotta, Chiara Romualdi, Robert Fruscio, Tommaso Grassi, Vittoria Fotia, Giulia Caratti, Patrizia Perego, Enrica Calura, Luca Clivio, Maurizio D’Incalci _, Luca Beltrame and Sergio Marchini

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Oncotarget. 2021; 12:2404-2417. https://doi.org/10.18632/oncotarget.10505

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Abstract

Lara Paracchini1,*, Laura Mannarino1,*, Ilaria Craparotta1, Chiara Romualdi2, Robert Fruscio3, Tommaso Grassi3, Vittoria Fotia4, Giulia Caratti1, Patrizia Perego5, Enrica Calura2, Luca Clivio1, Maurizio D’Incalci1, Luca Beltrame1,§, Sergio Marchini1,§

1Department of Oncology, IRCCS Istituto di Ricerche Farmacologiche “Mario Negri”, Milano, Italy

2Department of Biology, University of Padova, Padova, Italy

3Clinic of Obstetrics and Gynaecology, University of Milano-Bicocca, San Gerardo Hospital, Monza, Italy

4PhD program in Experimental Medicine, University of Pavia, Pavia, Italy

5Pathology 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: maurizio.dincalci@marionegri.it

Keywords: ovarian cancer, temporal heterogeneity, spatial heterogeneity, targeted next generation sequencing, drug resistance

Received: March 01, 2016    Accepted: May 23, 2016    Published: November 23, 2021     Epub: 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.


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