Adamson A W, Ding Y C, Steele L, Leong L A, Morgan R, Wakabayashi M T, Han E S, Dellinger T H, Lin P S, Hakim A A, Wilczynski S, Warden C D, Tao S, Bedell V, Cristea M C, Neuhausen S L
Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte CA.
Formerly, Department of Medical Oncology, City of Hope National Medical Center, Duarte CA.
Res Sq. 2023 Feb 20:rs.3.rs-2592107. doi: 10.21203/rs.3.rs-2592107/v1.
High-grade serous ovarian cancers (HGSCs) display a high degree of complex genetic alterations. In this study, we identified germline and somatic genetic alterations in HGSC and their association with relapse-free and overall survival. Using a targeted capture of 577 genes involved in DNA damage response and PI3K/AKT/mTOR pathways, we conducted next-generation sequencing of DNA from matched blood and tumor tissue from 71 HGSC participants. In addition, we performed the OncoScan assay on tumor DNA from 61 participants to examine somatic copy number alterations. Approximately one-third of tumors had loss-of-function germline (18/71, 25.4%) or somatic (7/71, 9.9%) variants in the DNA homologous recombination repair pathway genes , and . Loss-of-function germline variants also were identified in other Fanconi anemia genes and in MAPK and PI3K/AKT/mTOR pathway genes. Most tumors harbored somatic TP53 variants (65/71, 91.5%). Using the OncoScan assay on tumor DNA from 61 participants, we identified focal homozygous deletions in , and . In total, 38% (27/71) of HGSC patients harbored pathogenic variants in DNA homologous recombination repair genes. For patients with multiple tissues from the primary debulking or from multiple surgeries, the somatic mutations were maintained with few newly acquired point mutations suggesting that tumor evolution was not through somatic mutations. There was a significant association of loss-of-function variants in homologous recombination repair pathway genes and high-amplitude somatic copy number alterations. Using GISTIC analysis, we identified , and in these regions that were significantly associated with an increase in cancer recurrence and a reduction in overall survival. From 71 patients with HGCS, we performed targeted germline and tumor sequencing and provided a comprehensive analysis of these 577 genes. We identified germline and somatic genetic alterations including somatic copy number alterations and analyzed their associations with relapse-free and overall survival. This single-site long-term follow-up study provides additional information on genetic alterations related to occurrence and outcome of HGSC. Our findings suggest that targeted treatments based on both variant and SCNA profile potentially could improve relapse-free and overall survival.
高级别浆液性卵巢癌（HGSCs）表现出高度复杂的基因改变。在本研究中，我们鉴定了HGSC中的种系和体细胞基因改变及其与无复发生存期和总生存期的关联。通过对涉及DNA损伤反应和PI3K/AKT/mTOR通路的577个基因进行靶向捕获，我们对71名HGSC参与者的匹配血液和肿瘤组织的DNA进行了二代测序。此外，我们对61名参与者的肿瘤DNA进行了OncoScan分析，以检测体细胞拷贝数改变。约三分之一的肿瘤在DNA同源重组修复通路基因 和 中存在功能丧失的种系（18/71，25.4%）或体细胞（7/71，9.9%）变异。在其他范可尼贫血基因以及MAPK和PI3K/AKT/mTOR通路基因中也鉴定出了功能丧失的种系变异。大多数肿瘤存在体细胞TP53变异（65/71，91.5%）。通过对61名参与者的肿瘤DNA进行OncoScan分析，我们在 和 中鉴定出了局灶性纯合缺失。总体而言，38%（27/71）的HGSC患者在DNA同源重组修复基因中存在致病性变异。对于来自初次肿瘤细胞减灭术或多次手术的多个组织的患者，体细胞突变得以维持，新获得的点突变很少，这表明肿瘤进化不是通过体细胞突变。同源重组修复通路基因中的功能丧失变异与高幅度体细胞拷贝数改变之间存在显著关联。使用GISTIC分析，我们在这些区域中鉴定出 和 ，它们与癌症复发增加和总生存期缩短显著相关。我们对71名HGCS患者进行了靶向种系和肿瘤测序，并对这577个基因进行了全面分析。我们鉴定了种系和体细胞基因改变，包括体细胞拷贝数改变，并分析了它们与无复发生存期和总生存期的关联。这项单中心长期随访研究提供了与HGSC发生和结局相关的基因改变的更多信息。我们的研究结果表明，基于变异和SCNA谱的靶向治疗可能会改善无复发生存期和总生存期。
