Abstract 3793: Mutational and gene expression profiles of the primary tumor and matched brain metastasis of epithelial ovarian cancer reveal differences in LAMC3 and MYC target genes
Authors: Trozzi Rita , Nero Camilla , Buttarelli Marianna , Salvi Marcello , Giacò Luciano , Minucci Angelo , Marchetti Claudia , Sassu Carolina , Persiani Federica , De Marco Lorenzo , Duranti Simona , Floriana Camarda , Iacobelli Valentina , Marino Ilenia , Mastrantoni Luca , Giacomini Flavia , Piermattei Alessia , Valentini Mariagrazia , Pasciuto Tina , Maria De Bonis , Raspaglio Giuseppina , Giannarelli Diana , Fagotti Anna , Cacchiarelli Davide , Scambia Giovanni 
Published: March 2024

Abstract
Introduction: Brain metastases (BM) from Epithelial ovarian cancer (EOC) are a rare and late-stage disease manifestation, very poorly biologically characterized. We performed a multi-omics characterisation of primary EOC samples (PT) and the matched BM, to assess differences in mutational and gene expression profiles.
Material and Methods: We retrospectively collected data from EOC patients treated at Fondazione Policlinico Gemelli IRCCS who underwent surgical removal of BM between 2011 and 2022. We collected the formalin-fixed, paraffin-embedded (FFPE) tissue of the PT and the matched BM. An evaluation of single nucleotide variants (SNVs), insertions/deletions (indels) and copy number variations (CNVs) in 523 genes as well as known and unknown fusions and splicing variants in 55 genes was performed (Illumina TruSight Oncology 500 high throughput). Moreover, a bulk RNAseq analysis was conducted utilizing the NEGEDIA Digital mRNA-seq clinical-grade sequencing service. We acknowledged as differentially expressed genes if they exhibited a −1≤log2 (Fold Change)≥1 and pAdj≤0.05. To ensure specificity in identifying differential gene expressions pertinent to our tumoral tissues, genes associated with brain-related functionalities were systematically excluded from downstream analyses and identified through meticulous screening via the Human Protein Atlas. Clonal evolution was evaluated with two distinct algorithms: Pyclone VI and Sciclone.
Results: Matched PT/BM FFPE samples were collected from 10 different patients. We identified 21 SNVs: most of them were shared between the PT and the matched BM and TP53, CCND1, IRS2, and FGFR4 mutations emerged as the most frequently detected (shared in 70%, 50%, 50%, and 40% of the cases, respectively). Among 56 CNV detected, most of them were exclusive of the BM samples. Specifically, MYC family genes (MYC, MYCL, MYCN) were the most frequently amplified. At the clonal analysis, each patient showed at least two clusters. The majority of clusters turned out to be consistent among PT and BM demonstrating monoclonal evolution. Gene set variation analysis discovered 50 different gene sets between the PT and the BM (p &lt; 0.05). Among them, the E2F targets, G2M checkpoint, MYC targets V1 and MYC targets v2 hallmarks showed higher expression in the BM. We identified 110 significant differentially expressed genes between PT and BM samples, including 27 upregulated and 83 downregulated genes. The gene LAMC3 emerged as notably upregulated in metastatic contexts.
Conclusion: This is the largest cohort present in the Literature of EOC PT and matched BM characterized with a multi-omics analysis. The intersection of LAMC3 and MYC target genes within the MET signalling network, a pathway recognized for bolstering cell motility, introduces a compelling avenue for future research.
Citation Format: Rita Trozzi, Camilla Nero, Marianna Buttarelli, Marcello Salvi, Luciano Giacò, Angelo Minucci, Claudia Marchetti, Carolina Sassu, Federica Persiani, Lorenzo De Marco, Simona Duranti, Camarda Floriana, Valentina Iacobelli, Ilenia Marino, Luca Mastrantoni, Flavia Giacomini, Alessia Piermattei, Mariagrazia Valentini, Tina Pasciuto, De Bonis Maria, Giuseppina Raspaglio, Diana Giannarelli, Anna Fagotti, Davide Cacchiarelli, Giovanni Scambia. Mutational and gene expression profiles of the primary tumor and matched brain metastasis of epithelial ovarian cancer reveal differences in LAMC3 and MYC target genes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3793.