High-grade serous ovarian carcinoma (HGSOC) is the fifth leading cause of cancer-related deaths of women in the United States. Disease-associated mutations have been identified by the Cancer Genome Atlas Research Network. However, aside from mutations in TP53 or the RB1 pathway that are common in HGSOC, the contributions of mutation combinations are unclear. Here, we report CRISPR mutagenesis of 20 putative HGSOC driver genes to identify combinatorial disruptions of genes that transform either ovarian surface epithelium stem cells (OSE-SCs) or non-stem cells (OSE-NSs). Our results support the OSE-SC theory of HGSOC initiation and suggest that most commonly mutated genes in HGSOC have no effect on OSE-SC transformation initiation. Our results indicate that disruption of TP53 and PTEN, combined with RB1 disruption, constitutes a core set of mutations driving efficient transformation in vitro. The combined data may contribute to more accurate modeling of HGSOC development.

高度浆液性卵巢癌（HGSOC）是美国女性与癌症相关的死亡的第五大主要原因。癌症基因组图谱研究网络已经确定了与疾病相关的突变。但是，除了HGSOC中常见的TP53或RB1途径突变外，突变组合的作用尚不清楚。在这里，我们报告CRISPR诱变的20个推定HGSOC驱动程序基因，以鉴定转化卵巢表面上皮干细胞（OSE-SCs）或非干细胞（OSE-NSs）的基因的组合破坏。我们的结果支持HGSOC启动的OSE-SC理论，并表明HGSOC中最常见的突变基因对OSE-SC转化的启动没有影响。我们的结果表明TP53和PTEN结合RB1破坏，构成了一组核心突变，可在体外驱动有效转化。合并的数据可能有助于HGSOC发展的更准确建模。