Zhai Yali, Fearon Eric R, Cho Kathleen R
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Cancers (Basel). 2025 Aug 24;17(17):2759. doi: 10.3390/cancers17172759.
BACKGROUND/OBJECTIVES: High-grade serous carcinoma (HGSC) is the leading cause of ovarian cancer-related mortality. It usually arises from fallopian tube epithelium, with a smaller subset arising in non-tubal sites including the ovary or peritoneum. The origin of HGSCs without evidence of tubal involvement remains unclear. Moreover, in women with genetic predisposition to developing HGSC, the additional protection afforded by prophylactic removal of the ovaries in addition to the fallopian tubes has not yet been established.
We used a well-characterized genetically engineered mouse model (GEMM) of oviductal HGSC based on conditional, somatic inactivation of the , , , and tumor suppressor genes ( mice) to compare preventive effects for HGSC via bilateral salpingectomy versus bilateral salpingo-oophorectomy. We also explored the origins of non-tubal HGSCs in ectopic tubal-type epithelium (endosalpingiosis) present in the mouse ovaries and peritoneum.
While bilateral salpingectomy significantly reduced the incidence of HGSCs in the GEMM model, bilateral salpingo-oophorectomy completely prevented tumor development. We identified an example of HGSC with apparent origin in endosalpingiosis, implicating endosalpingiosis as a likely precursor for non-tubal HGSC.
Our findings confirm the superiority of bilateral salpingo-oophorectomy over salpingectomy alone in reducing HGSC risk and affirm the rationale for surgical strategies to reduce HGSC risk in women carrying pathogenic variants of and other genes associated with homologous recombination deficiency. Our findings also illustrate how work with GEMMs can advance new insights into HGSC pathogenesis.
背景/目的：高级别浆液性癌（HGSC）是卵巢癌相关死亡的主要原因。它通常起源于输卵管上皮，一小部分起源于非输卵管部位，包括卵巢或腹膜。尚无输卵管受累证据的HGSC的起源仍不清楚。此外，对于有发生HGSC遗传易感性的女性，除输卵管外预防性切除卵巢所提供的额外保护尚未得到证实。
我们使用了一种基于条件性、体细胞性失活 、 、 和 肿瘤抑制基因（ 小鼠）的特征明确的输卵管HGSC基因工程小鼠模型（GEMM），以比较双侧输卵管切除术与双侧输卵管卵巢切除术对HGSC的预防效果。我们还探究了小鼠卵巢和腹膜中存在的异位输卵管型上皮（输卵管内膜异位症）中非输卵管HGSC的起源。
虽然双侧输卵管切除术在GEMM模型中显著降低了HGSC的发生率，但双侧输卵管卵巢切除术完全阻止了肿瘤的发生。我们发现了一个明显起源于输卵管内膜异位症的HGSC实例，这表明输卵管内膜异位症可能是非输卵管HGSC的前体。
我们的研究结果证实了双侧输卵管卵巢切除术在降低HGSC风险方面优于单纯输卵管切除术，并肯定了手术策略在降低携带 及其他与同源重组缺陷相关基因的致病性变异的女性发生HGSC风险方面的基本原理。我们的研究结果还说明了利用GEMM开展研究如何能够推进对HGSC发病机制的新认识。
