Promoterless Transposon Mutagenesis Drives Solid Cancers Via Tumor Suppressor Inactivation

Simple SummaryOver the past two decades, there have been many published studies reporting high-copy SB transgenic lines in which the transposon allele includes both gene-trap and internal promoter elements to drive tumorigenesis in vivo. Cancer gene discovery from end-stage solid tumors in these studies performed by our labs and others has found few proto-oncogenic insertions. However, the question remains whether these tumors are initiated by SB insertions in proto-oncogenes to promote permissible phenotypes for tumor initiation, which become dispensable for tumor maintenance. Here, our study expands upon these indirect observations to demonstrate that high-copy SB transposon alleles designed with only gene-trap elements that inactivate genes (Onc2.3) can drive tumor initiation, progression, and maintenance to end-stage tumors in the absence of sensitizing mutations.A central challenge in cancer genomics is the systematic identification of single and cooperating tumor suppressor gene mutations driving cellular transformation and tumor progression in the absence of oncogenic driver mutation(s). Multiple in vitro and in vivo gene inactivation screens have enhanced our understanding of the tumor suppressor gene landscape in various cancers. However, these studies are limited to single or combination gene effects, specific organs, or require sensitizing mutations. In this study, we developed and utilized a Sleeping Beauty transposon mutagenesis system that functions only as a gene trap to exclusively inactivate tumor suppressor genes. Using whole body transposon mobilization in wild type mice, we observed that cumulative gene inactivation can drive tumorigenesis of solid cancers. We provide a quantitative landscape of the tumor suppressor genes inactivated in these cancers and show that, despite the absence of oncogenic drivers, these genes converge on key biological pathways and processes associated with cancer hallmarks.