Valentine Mark C, Mullen Mary M, Kotnik Emilee N, Powell Matthew A, Thaker Premal H, McCourt Carolyn K, Kuroki Lindsay M, Hagemann Andrea R, Arend Rebecca C, Holehouse Alex S, Mitra Robi, Mutch David G, Fuh Katherine C
Washington University in St. Louis, St. Louis, Missouri, United States.
Washington University in St. Louis, St. Louis, MO, United States.
Cancer Res. 2025 Jul 22. doi: 10.1158/0008-5472.CAN-24-3804.
High-grade serous ovarian cancer (HGSC) accounts for more than 200,000 deaths each year. Despite recent advances in treating HGSC with neoadjuvant chemotherapy, the majority of patients ultimately develop chemotherapy resistance. HGSC is characterized by TP53 mutations and widespread copy number alterations and occurs frequently in the setting of deleterious germline BRCA1/2 variations, but many cases lack putative driver mutations. Here, we performed whole-exome, whole-genome, and whole transcriptome sequencing along with mass spectrometry to characterize the molecular landscape of HGSC in 22 paired samples obtained before and after neoadjuvant chemotherapy. Responsiveness to chemotherapy was determined for each patient. Evidence at the DNA, RNA, and protein level revealed numerous defects in cell-cell and cell-matrix interactions as well as disruption of cell polarity and cytoskeletal regulation in HGSC, indicating that defects in epithelial integrity were present in the majority of HGSC patients. Non-responsive HGSC harbored subclones with putative survival mutations. Additionally, ineffective nonsense mediated decay resulted in the persistence of transcripts with frameshift mutations that were translated into aberrant proteins detectable in HGSC samples. Together, these findings suggest that HGSC may arise through defects in maintenance of epithelial integrity that lead to shedding of malignant cells throughout the peritoneum, and the presence of resistant subclones prior to chemotherapy may decrease the chemosensitivity of patients.
高级别浆液性卵巢癌（HGSC）每年导致超过20万人死亡。尽管最近在使用新辅助化疗治疗HGSC方面取得了进展，但大多数患者最终还是会产生化疗耐药性。HGSC的特征是TP53突变和广泛的拷贝数改变，并且经常发生在有害的种系BRCA1/2变异的情况下，但许多病例缺乏推定的驱动突变。在这里，我们对22对新辅助化疗前后获得的样本进行了全外显子组、全基因组和全转录组测序以及质谱分析，以描绘HGSC的分子图谱。确定了每位患者对化疗的反应性。DNA、RNA和蛋白质水平的证据揭示了HGSC中细胞间和细胞与基质相互作用的众多缺陷以及细胞极性和细胞骨架调节的破坏，表明大多数HGSC患者存在上皮完整性缺陷。无反应的HGSC含有具有推定生存突变的亚克隆。此外，无效的无义介导衰变导致具有移码突变的转录本持续存在，这些转录本被翻译成在HGSC样本中可检测到的异常蛋白质。总之，这些发现表明HGSC可能通过上皮完整性维持缺陷而产生，导致恶性细胞在整个腹膜脱落，化疗前耐药亚克隆的存在可能会降低患者的化疗敏感性。
