The genomic and immune landscape of long-term survivors of high-grade serous ovarian cancer [Methylation array]. The genomic and immune landscape of long-term survivors of high-grade serous ovarian cancer [Methylation array]

Less than half of all patients with advanced-stage high-grade serous ovarian cancers (HGSC) survive more than five years post-diagnosis but those who have an exceptionally long survival could provide new insights into tumor biology and therapeutic approaches. We analyzed 60 patients with advanced-stage, HGSC who survived more than 10 years after diagnosis using whole-genome sequencing, transcriptome, and methylome profiling of their primary tumor samples, comparing this data to 66 short- or moderate-term survivors. Tumors of long-term survivors were more likely to have multiple alterations in genes associated with DNA repair, and more frequent somatic variants resulting in an increased predicted neoantigen load. Patients clustered into survival groups based on genomic and immune cell signatures, including three subsets of patients with BRCA1 alterations with distinctly different outcomes. Specific combinations of germline and somatic gene alterations, tumor cell phenotypes, and differential immune responses appear to contribute to long-term survival in HGSC. Methylation profiling was done on 58 high grade serous ovarian cancer samples, 53 of which were primary tumors and and 5 were relapse tumors. 73 primary tumors from GSE65820 were also used as part of the cohort. Overall design: Genome wide DNA methylation profiling of 53 primary tumors and 5 relapse tumors of long-term survivors of high grade serous ovarian cancer. The Illumina Infinium MethylationEPIC BeadChip was used to obtain DNA methylation profiles across approximately 850,000 CpGs. 73 primary tumors from GSE65820 were also used in the project.

晚期高级别浆液性卵巢癌（high-grade serous ovarian cancer, HGSC）患者中，仅有不足半数可在确诊后存活五年以上，而生存期极长的该类患者可为肿瘤生物学与治疗策略研究提供全新视角。我们对60例确诊后生存期超过10年的晚期HGSC患者的原发肿瘤样本，开展全基因组测序、转录组及甲基化组分析，并将该数据集与66例短期或中期生存期患者的对应数据进行对比。研究发现，长期存活患者的肿瘤更易出现多种与DNA修复相关的基因变异，且体细胞突变发生频率更高，进而导致预测的新抗原负荷升高。基于基因组特征与免疫细胞特征，患者可被划分为不同生存群组，其中包含3个携带BRCA1变异的亚群，其临床结局存在显著差异。种系与体细胞基因变异的特定组合、肿瘤细胞表型以及差异化免疫应答，似乎是HGSC患者实现长期存活的关键影响因素。我们对58例高级别浆液性卵巢癌样本开展了甲基化组分析，其中53例为原发肿瘤，5例为复发肿瘤。本项目同时纳入GSE65820数据集的73例原发肿瘤作为研究队列的一部分。总体实验设计：针对晚期HGSC长期存活患者的53例原发肿瘤与5例复发肿瘤，开展全基因组DNA甲基化谱分析，采用Illumina Infinium MethylationEPIC微珠芯片对约850,000个CpG位点的甲基化特征进行检测。本项目同时纳入GSE65820数据集的73例原发肿瘤样本。