Abstract 2230: Integrative genomic analysis of refractory metastatic cancer
Authors: Viot Julien , Pradat Yoann , Padioleau Ismael , Yurchenko Andrey , Verlingues Loic , Clodion Rebecca , Michiels Stefan , Deloger Marc , Jules-Clément Gerome , Loriot Yohann , Besse Benjamin , Andre Fabrice , Cournedes Paul-Henry , Gautheret Daniel , Nikolaev Sergey 
Published: July 2021

Abstract
Metastatic cancer refractory to treatment has a dismal prognosis. While genetic mechanisms of primary tumors and to a lesser extent of metastatic cancers have been studied on large cohorts, it is still not well understood if metastatic tumors refractory to systemic treatment contain specific signatures at genomic or transcriptional levels. Molecular characterization of metastatic cancers at terminal stage is indispensable for understanding the mechanisms of resistance to treatment and for prediction of tumor aggressiveness at earlier stages. Here, we present a large pan-cancer cohort of 914 tumors resistant to systemic therapies. Comprehensive clinical information is available for all the patients and includes tumor subtype, biopsy site, treatment, age, overall survival, etc. Biopsies of tumor metastases were taken after the diagnosed resistance. For this cohort we performed whole exome sequencing of a subset of 427 tumors with a median depth of 123X and matching blood, and transcriptome sequencing of all 914 tumors. We will discuss the variation in this cohort along 3 axes. Firstly we will describe the somatic mutations and indels by types of driver mutations, mutational burden, level of subclonality and mutational signatures. Additionally we will elaborate on the genomic instability and quantity of somatic copy number alterations (SCNAs). Secondly, we will present the annotation of germline DNA, frequency and classification of pathogenic variants predisposing to cancer. Germline variants are analyzed in the context of somatic genome focusing on the detection of the second hit by a mutation or a SCNA. Thirdly, we will present results of the analysis of differentially expressed genes and transcripts, activation of oncogenic and treatment resistance pathways, and fusion genes reported by multiple tools. The aforementioned genetic parameters are fed into a multi-omics model for identification of the key factors associated with the clinical features in the cohort. Furthermore this cohort is compared to primary tumors and to another cohort of metastatic tumors in order to unravel genetic markers of refractory disease. To this aim, we harmonized DNA- and RNA-derived variables from The Cancer Genome Atlas (TCGA) and MET500 (Robinson et al., Nature 2017). Such integrative analysis unravels genetic hallmarks of aggressive and treatment-resistant metastatic cancers highlighting the importance of multi-level tumor profiling to inform on therapeutic strategies.
Citation Format: Julien Viot, Yoann Pradat, Ismael Padioleau, Andrey Yurchenko, Loic Verlingues, Rebecca Clodion, Stefan Michiels, Marc Deloger, Gerome Jules-Clément, Yohann Loriot, Benjamin Besse, Fabrice Andre, Paul-Henry Cournedes, Daniel Gautheret, Sergey Nikolaev. Integrative genomic analysis of refractory metastatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2230.