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. Methods: We used a well-characterized genetically engineered mouse model (GEMM) of oviductal HGSC based on conditional, somatic inactivation of theBrca1,Trp53,Rb1, andNf1tumor suppressor genes (BPRNmice) 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. Results: 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. Conclusions: 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 ofBRCA1/2and 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：高级别浆液性癌是卵巢癌相关死亡的主要原因。它通常起源于输卵管上皮，少数起源于非输卵管部位，包括卵巢或腹膜。无输卵管受累证据的高级别浆液性癌的起源尚不明确。此外，对于具有高级别浆液性癌遗传易感性的女性，除输卵管切除外，预防性切除卵巢是否能提供额外保护尚未得到证实。方法：我们使用基于条件性体细胞失活Brca1、Trp53、Rb1和Nf1肿瘤抑制基因（BPRN小鼠）的、特征明确的输卵管高级别浆液性癌基因工程小鼠模型，比较双侧输卵管切除术与双侧输卵管卵巢切除术对高级别浆液性癌的预防效果。我们还探讨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）中非输卵管高级别浆液性癌的起源。结果：在基因工程小鼠模型中，双侧输卵管切除术显著降低了高级别浆液性癌的发病率，而双侧输卵管卵巢切除术则完全阻止了肿瘤的发生。我们发现了一例明显起源于输卵管内膜异位症的高级别浆液性癌，提示输卵管内膜异位症可能是非输卵管高级别浆液性癌的前驱病变。结论：我们的研究结果证实，在降低高级别浆液性癌风险方面，双侧输卵管卵巢切除术优于单纯输卵管切除术，并支持对携带BRCA1/2及其他同源重组缺陷相关基因致病性变异的女性采取手术策略以降低高级别浆液性癌风险。我们的发现也说明了基因工程小鼠模型研究如何能推动对高级别浆液性癌发病机制的新认识。
肿瘤(癌症)患者之家