Eine Plattform für die Wissenschaft: Bauingenieurwesen, Architektur und Urbanistik
Eine Plattform für die Wissenschaft: Bauingenieurwesen, Architektur und Urbanistik
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, SETD8C302R) 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 SETD8C302R 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.
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, SETD8C302R) 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 SETD8C302R 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.
SETD8C302R Mutation Revealed from Myofibroblastoma‐Discordant Monozygotic Twins Leads to p53/p21 Deficit and WEE1 Inhibitor Sensitivity
Li, Miao (Autor:in) / Wang, Hongwu (Autor:in) / Liao, Hongwei (Autor:in) / Shen, Jiaxin (Autor:in) / Wu, Yinfang (Autor:in) / Wu, Yanping (Autor:in) / Weng, Qingyu (Autor:in) / Zhu, Chen (Autor:in) / Geng, Xinwei (Autor:in) / Lan, Fen (Autor:in)
Advanced Science ; 7
01.10.2020
10 pages
Aufsatz (Zeitschrift)
Elektronische Ressource
Englisch
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