Genomic characterization of brain metastases (BM) in high-grade serous ovarian cancer (HGSOC).

Renata Duchnowska Military Institute of Medicine, Warsaw, Poland info_outline Renata Duchnowska, Anna Maria Supernat, Rafał Pęksa, Marta Łukasiewicz, Tomasz Stokowy, Monika Umińska, Ewa Iżycka-Świeszewska, Anna Kowalczyk, Waldemar Och, Monika Rucinska, Wojciech P Olszewski, Tomasz Mandat, Bozena Jarosz, Michał Bieńkowski, Wojciech Biernat, Jacek Jassem

Authors Renata Duchnowska Military Institute of Medicine, Warsaw, Poland info_outline Renata Duchnowska, Anna Maria Supernat, Rafał Pęksa, Marta Łukasiewicz, Tomasz Stokowy, Monika Umińska, Ewa Iżycka-Świeszewska, Anna Kowalczyk, Waldemar Och, Monika Rucinska, Wojciech P Olszewski, Tomasz Mandat, Bozena Jarosz, Michał Bieńkowski, Wojciech Biernat, Jacek Jassem Organizations Military Institute of Medicine, Warsaw, Poland, Medical University of Gdansk, Gdynia, Poland, Department of Pathology, Medical University of Gdańsk, Gdańsk, Poland, Laboratory of Cell Biology, Intercollegiate Faculty of Biotechnology, University of Gdańsk, Gdańsk, Poland, Computational Biology Unit, Institute of Informatics, University of Bergen, Bergen, Norway, Oncology Unit, Copernicus Hospital Gdańsk, Gdańsk, Poland, Department of Pathology and Neuropathology Medical University of Gdańsk; Department of Pathomorphology, Copernicus Hospitals, Gdańsk, Poland, Medical University of Gdańsk, Oncology and Radiotherapy, Gdańsk, Poland, Regional Hospital, Olsztyn, Poland, Department of Oncology Collegium Medicum School of Medicine Univeristy of Warmia and Mazury, Olsztyn, Poland, Department of Pathology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland, Institute of Oncology, Warsaw, Poland, Medical University of Lublin, Lublin, Poland, Medical University of Gdansk, Gdańsk, Poland, Medical University of Gdańsk, Department of Pathology, Gdańsk, Poland, Medical University of Gdańsk, Gdańsk, Poland Abstract Disclosures Research Funding Other Background: BM are a rare occurrence in ovarian cancer (OC) and their molecular characteristics is virtually unknown. DNA damage repair (DDR) deficiency is prevalent in OC, and co-mutated TP53 and any DDR denotes high tumor mutation burden (TMB). We genetically characterized a unique series of high-grade serous ovarian cancer (HGSOC) patients who developed BM to identify alterations of potential clinical relevance. Methods: Whole-exome sequencing (2x150bp, SureSelectXT Library Prep Kit, Illumina’s NovaSeq platform) was performed in matched BM, primary tumors (PT) and normal tissue. DNA was extracted from FFPE samples using QIAamp DNA FFPE Tissue Kit (Qiagen, Germany). All mutations were checked with Catalogue of Somatic Mutations in Cancer (COSMIC) and Integrative Genomics Viewer (IGV). Results: Study group included 10 HGSOC patients (International Federation of Gynecology and Obstetrics classification (FIGO) II-IV, mean age at diagnosis 48 years, range 35-59). Median time from primary HGSOC diagnosis to BM was 38 months (range, 18 to 149). TP53 somatic mutations were found in both primary tumor (PT) and BM in 8 patients. The other 2 cases harbored TP53 mutations not reported in COSMIC catalogue: p.S60L and intronic TP53 mutation preceding p.I322 (IGV). In 9 cases TP53 mutations coexisted with germline or somatic DNA damage repair deficiency. Four cases contained BRCA1 mutations (all germline), and none harbored germline BRCA2 mutation. Other mutated genes included MLH1 (2 somatic, 2 germline), ATR (4 germline, 1 somatic), AMT (1 somatic), RAD50 (1 somatic), ERCC4 (1 somatic), FANCD2 (1 somatic) and RPA1 (1 germline). Three mutation signatures defined in the COSMIC database were indentified in BM: 6, 20 and 30. In 6 cases these mutations were shared in PT, and in another 4 their presence in PT could not be determined due to technical reasons. Median survival from BM was 31 months (range, 5 to 184). Conclusions: Genomic analysis of BM provides an opportunity to identify potentially clinically informative alterations. Mutational profiles in PT are generally reflected in BM. Detected genetic alterations suggest their potential sensitivity to PARP inhibitors and immunotherapy.