基因工程小鼠模型 (GEMM) 从根本上改变了人们对卵巢癌病因、早期检测和治疗的理解。 MYC 是一种癌基因，是高级别浆液性卵巢癌 (HGSOC) 中扩增程度最高的基因之一，但它以前从未被用来驱动 HGSOC GEMM。我们将 Myc 和显性失活突变体 p53-R270H 与输卵管上皮特异性启动子 Ovgp1 偶联，生成 HGSOC 的新 GEMM。雌性小鼠平均在 14.5 个月时患上致命的癌症。小鼠的组织病理学检查揭示了 HGSOC 特征，包括输卵管上皮和卵巢表面上皮内细胞簇中的核 p53 和核 MYC。出乎意料的是，在子宫腔上皮中也发现了核 p53 和 MYC 簇状细胞表达，可能来自输卵管上皮 (FTE) 的上皮内转移。提取的肿瘤细胞在 p53 基因座上表现出杂合性的严重丧失，留下突变等位基因。这些癌细胞中拷贝数的改变很普遍，破坏了大部分基因。转录组图谱与人类 HGSOC 和浆液性子宫内膜癌最为匹配。总而言之，这些结果表明 Myc 和 Trp53-R270H 转基因能够通过利用 HGSOC 的严格仿人遗传标志来重现 HGSOC 的许多表型标志。这种新的小鼠模型能够进一步探索卵巢癌的发病机制，特别是 50% 的 HGSOC 缺乏同源定向修复突变。组织学和转录组学结果与子宫浆液性癌可能起源于输卵管上皮的假设一致。

Genetically engineered mouse models (GEMM) have fundamentally changed how ovarian cancer etiology, early detection, and treatment is understood. MYC, an oncogene, is amongst the most amplified genes in high-grade serous ovarian cancer (HGSOC), but it has not previously been utilized to drive HGSOC GEMMs. We coupled Myc and dominant negative mutant p53-R270H with a fallopian tube epithelium-specific promoter Ovgp1 to generate a new GEMM of HGSOC. Female mice developed lethal cancer at an average of 14.5 months. Histopathological examination of mice revealed HGSOC characteristics including nuclear p53 and nuclear MYC in clusters of cells within the fallopian tube epithelium and ovarian surface epithelium. Unexpectedly, nuclear p53 and MYC clustered cell expression was also identified in the uterine luminal epithelium, possibly from intraepithelial metastasis from the fallopian tube epithelium (FTE). Extracted tumor cells exhibited strong loss of heterozygosity at the p53 locus, leaving the mutant allele. Copy number alterations in these cancer cells were prevalent, disrupting a large fraction of genes. Transcriptome profiles most closely matched human HGSOC and serous endometrial cancer. Taken together, these results demonstrate the Myc and Trp53-R270H transgene was able to recapitulate many phenotypic hallmarks of HGSOC through the utilization of strictly human-mimetic genetic hallmarks of HGSOC. This new mouse model enables further exploration of ovarian cancer pathogenesis, particularly in the 50% of HGSOC which lack homology directed repair mutations. Histological and transcriptomic findings are consistent with the hypothesis that uterine serous cancer may originate from the fallopian tube epithelium.