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.

中文翻译：

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从肌纤维母细胞瘤不一致单卵双胞胎揭示SETD8C302R突变导致p53 / p21缺陷和WEE1抑制剂敏感性

高通量基因测序已发现各种遗传变异是某些常见遗传性癌症的罪魁祸首。但是，仍无法解释大部分癌症的遗传力，这可能是由于隐藏在无数无意义的遗传变异中的罕见有害突变所致。这对病理学的理解提出了很大的挑战，从而对受影响患者的有效治疗方法进行了合理设计。在此，有代表性的案例中采用了全基因组测序，其中一个单卵双胞胎与肺炎性肌成纤维细胞瘤不一致，从而揭示了罕见的肿瘤相关突变。赖氨酸甲基转移酶SETD8（登录号：NM_020382，SETD8 ^C302R）的错义单核苷酸变异rs61955126 T> C）已暴露。结果表明，SETD8通过促进忠实的DNA复制对于基因组完整性至关重要，其C302R突变可下调p53 / p21途径。重要的是，SETD8 ^C302R突变显着提高了癌细胞对WEE1抑制的敏感性。鉴于WEE1抑制剂已显示出临床批准的巨大希望，这些结果为使用WEE1抑制剂治疗带有相同突变的癌症患者提供了一种潜在的治疗方法，并表明基因组测序和遗传功能研究可整合到个性化治疗中。