Evaluation of the gene fusion landscape in early onset sporadic rectal cancer reveals association with chromatin architecture and genome stability

Gene fusions represent a distinct class of structural variants identified frequently in cancer genomes across cancer types. Several gene fusions exhibit gain of oncogenic function and thus have been the focus of development of efficient targeted therapies. However, investigation of fusion landscape in early-onset sporadic rectal cancer, a poorly studied colorectal cancer subtype prevalent in developing countries, has not been performed. Here, we present a comprehensive landscape of gene fusions in EOSRC and CRC using patient derived tumor samples and data from The Cancer Genome Atlas, respectively. Gene Ontology analysis revealed enrichment of unique biological process terms associated with 5- and 3- fusion partner genes. Extensive network analysis highlighted genes exhibiting significant promiscuity in fusion formation and their association with chromosome fragile sites. Investigation of fusion formation in the context of global chromatin architecture unravelled a novel mode of gene activation that arose from fusion between genes located in orthogonal chromatin compartments. The study provides novel evidence linking fusions to genome stability and architecture and unearthed a hitherto unidentified mode of gene activation in cancer.