SETD8C302R Mutation Revealed from Myofibroblastoma-Discordant Monozygotic Twins Leads to p53/p21 Deficit and WEE1 Inhibitor Sensitivity

High-throughput gene Sequencing has identified various genetic variants as the culprits for some common hereditary cancers. However, the heritability of a substantial proportion of cancers remains unexplained, which may result from rare deleterious mutations hidden in a myriad of nonsense genetic variations. This poses a great challenge to the understanding of the pathology and thus the rational design of effective treatments for affected patients. Here, whole genome Sequencing is employed in a representative case in which one monozygotic twin is discordant for lung inflammatory myofibroblastoma to disclose rare tumor-related mutations. A missense single nucleotide variation rs61955126 T>C in the lysine methyltransferase SETD8 (accession: NM_020382, SETD8^C302R ) is exposed. It is shown that SETD8 is vital for genomic integrity by promoting faithful DNA replication, and its C302R mutation downregulates the p53/p21 pathway. Importantly, the SETD8^C302R mutation significantly increases the sensitivity of Cancer cells to Wee1 inhibition. Given that Wee1 inhibitors have shown great promise for clinical approval, these results impart a potential therapeutic approach using Wee1 Inhibitor for Cancer patients carrying the same mutation, and indicate that genome Sequencing and genetic functional studies can be integrated into individualized therapies.