SETD8C302R mutation revealed from myofibroblastoma-discordant monozygotic twins leads to p53/p21 deficit and WEE1 inhibitor sensitivity

【摘要】：Objective Background High-throughput gene sequencing have identified a number of common genetic variants as the culprits for some cancers of high incidence, facilitating the development of targeted therapeutics. In contrast, rare deleterious mutations are much less understood because they are hidden in a myriad of nonsense genetic variations, which poses great challenge to the understanding of the pathology and thus the rational design of effective treatments for affected patients. Methods Germline DNA from a pair of monozygotic(MZ) twins discordant for lung inflammatory myofibroblastoma(IMT) were sequenced. With the healthy twin sister and the 1,000 genomes as the reference, candidate pathogenic mutations in the patient were screened out from the rare and potentially deleterious variants on the basis of the enrichment score. Promising candidates were further subjected to functional validation and therapeutic targeting evaluation. Results We identified a missense single nucleotide variation rs61955126 TC in the lysine methyltransferase SETD8(Accession: NM_020382, SETD8 C302 R) from the patient. In functional studies, we demonstrated that SETD8 was required for faithful DNA replication and genomic integrity, and its C302 R mutation downregulated the p53/21 pathway. Importantly, The SETD8 C302 R mutation conferred hypersensitivity of cancer cells to WEE1 inhibition. Conclusion Whole genome sequencing on monozygotic twins provides a unique opportunity for interrogating rare pathogenetic mutations. Using this strategy, we identified a rare mutation of SETD8(SETD8 C302 R), and unraveled its role in genome stability maintenance. Particularly, we revealed that cancer cells carrying SETD8 C302 R may be effectively treated by WEE1 inhibitor that is already under clinical trials.