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

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

  • Adv Sci (Weinh). 2020 Aug 5;7(19):2001041. doi: 10.1002/advs.202001041.
Miao Li 1 Hongwu Wang 2 Hongwei Liao 1 Jiaxin Shen 1 Yinfang Wu 1 Yanping Wu 1 Qingyu Weng 1 Chen Zhu 1 Xinwei Geng 1 Fen Lan 1 Yang Xia 1 Bin Zhang 1 Hang Zou 2 Nan Zhang 2 Yunzhi Zhou 2 Zhihua Chen 1 Huahao Shen 1 Songmin Ying 1 Wen Li 1
Affiliations

Affiliations

  • 1 Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine Second Affiliated Hospital of Zhejiang University School of Medicine Hangzhou Zhejiang 310009 China.
  • 2 Department of Respiratory and Critical Care Medicine Emergency General Hospital Beijing 100028 China.
Abstract

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.

Keywords

genome instability | p53/p21 | rare mutations | SETD8 | WEE1 inhibition.

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