Abstract 2186: Distinct aggressive biology drives the evolution of metastatic cancer

Abstract

Abstract Metastatic disease is responsible for 90% of all cancer deaths. Understanding the process of how primary tumors achieve metastatic potential is of great importance and paramount to the development of precision medicine that may limit the aggressive distant spread of metastatic cancer. It is hypothesized that during cancer evolution, cells within the primary tumor obtain metastatic potential through acquisition of specific somatic alterations. However, the defining ability that allows metastasis remains unknown. By comparing genomic profiles of primary and metastatic cancers we wish to investigate if potential metastatic gate-keeper mutations exist, defined as alterations to individual genes or pathways that are required to facilitate metastatic dissemination.Here, we analyzed panel-based DNA sequencing datasets from the GENIE (Genomics Evidence Neoplasia Information Exchange) project, version 9.0. Analyses were performed on 174 shared cancer genes selected to include as many patients as possible while analyzing as many genes as possible. In total 39,036 patients had mutations or copy number alterations in one or more of the 174 shared genes across 25 different cancer types. Using bioinformatic tools, we compared genomic alterations in primary versus metastatic samples. Metastatic samples harbor a higher tumor mutation burden and increased levels of chromosomal instability. However, while we found a higher total level of driver mutations in metastatic samples, these appear primarily driven by a higher mutation burden, and corrected for this, we found a significantly lower level of drivers compared to primary. Overall, phylogenetic analysis showed that primary and metastatic samples clustered together by cancer type. Comparing two logistic regressions models, which was corrected for tumor mutation burden and genomic instability, we found that despite most genes show a relatively low difference in frequency between primary and metastatic disease, 55 of the 174 genes in this panel showed a small but significant overrepresentation in at least one cancer type in either primary or metastatic disease.With this analysis we demonstrate how the power of large datasets can be utilized to make novel inferences on cancer biology. We observed significant enrichment in overall mutation counts and copy number alterations in metastatic samples. However, we found limited genomic differences between primary and metastatic cancer within the same cancer types. This might suggest that acquisition of cancer driver mutations are initially mostly shaped by the tissue of origin where specific cancer driver mutations define the developing primary tumor, while acquisition of driver mutations that contribute to metastatic disease are less specific. It might indicate that the metastatic process is driven less by newly acquired metastatic features, but more by non-cancer features such as inflammation in the surrounding tissue. Citation Format: Ditte Sigaard Christensen, Johanne Ahrenfeldt, Mateo Sokač, Judit Kisistók, Nicholas McGranahan, Nicolai Juul Birkbak. Distinct aggressive biology drives the evolution of metastatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2186.