Su Rongjia, Liu Yuan, Wu Xiaomei, Xiang Jiangdong, Xi Xiaowei
Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Reproductive Medicine Center, Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Front Mol Biosci. 2021 Nov 19;8:762741. doi: 10.3389/fmolb.2021.762741. eCollection 2021.
The homologous recombination (HR) pathway defects in cancers induced abrogation of cell cycle checkpoints, resulting in the accumulation of DNA damage, mitotic catastrophe, and cell death. Cancers with BRCA1/2 loss and other accumulation of similar genomic scars resulting in HRD displayed increased sensitivity to chemotherapy. Our study aimed to explore HRD score genetic mechanisms and subsequent clinical outcomes in human cancers, especially ovarian cancer. We analyzed TCGA data of HRD score in 33 cancer types and evaluated HRD score distribution and difference among tumor stages and between primary and recurrent tumor tissues. A weighted gene co-expression network analysis (WGCNA) was performed to identify highly correlated genes representing essential modules contributing to the HRD score and distinguish the hub genes and significant pathways. We verified HRD status predicting roles in patients' overall survival (OS) with univariate and multivariate Cox regression analyses and built the predicting model for patient survival. We found that the HRD score increased with the rise in tumor stage, except for stage IV. The HRD score tended to grow up higher in recurrent tumor tissue than in their primary counterparts ( = 0.083). We constructed 15 co-expression modules with WGCNA, identified co-expressed genes and pathways impacting the HRD score, and concluded that the HRD score was tightly associated with tumor cells replication and proliferation. A combined HRD score ≥42 was associated with shorter OS in 33 cancer types (HR = 1.010, 95% CI: 1.008-1.011, < 0.001). However, in ovarian cancer, which ranked the highest HRD score among other cancers, HRD ≥42 cohort was significantly associated with longer OS (HR = 0.99, 95% CI: 0.98-0.99, < 0.0001). We also built a predicting model for 3 and 5 years survival in HGSC patients. A quantitative HRD score representing the accumulated genomic scars was dynamically increasing in proliferating tumor cells since the HRD score was tightly correlated to tumor cell division and replication. We highlighted HRD score biomarker role in prognosis prediction of ovarian cancer.
癌症中的同源重组（HR）途径缺陷会导致细胞周期检查点的废除，从而导致DNA损伤、有丝分裂灾难和细胞死亡的积累。具有BRCA1/2缺失和其他导致HRD的类似基因组疤痕积累的癌症对化疗表现出更高的敏感性。我们的研究旨在探索人类癌症，尤其是卵巢癌中HRD评分的遗传机制及后续临床结果。我们分析了33种癌症类型的HRD评分的TCGA数据，并评估了HRD评分在肿瘤分期之间以及原发肿瘤组织与复发肿瘤组织之间的分布和差异。进行了加权基因共表达网络分析（WGCNA），以识别代表对HRD评分有重要贡献的模块的高度相关基因，并区分枢纽基因和重要途径。我们通过单变量和多变量Cox回归分析验证了HRD状态对患者总生存期（OS）的预测作用，并建立了患者生存预测模型。我们发现，除IV期外，HRD评分随肿瘤分期的升高而增加。复发肿瘤组织中的HRD评分往往比其原发组织更高（P = 0.083）。我们用WGCNA构建了15个共表达模块，识别了影响HRD评分的共表达基因和途径，并得出HRD评分与肿瘤细胞复制和增殖密切相关的结论。在33种癌症类型中，HRD综合评分≥42与较短的总生存期相关（HR = 1.010，95%CI：1.008 - 1.011，P < 0.001）。然而，在HRD评分在其他癌症中最高的卵巢癌中，HRD≥42队列与更长的总生存期显著相关（HR = 0.99，95%CI：0.98 - 0.99，P < 0.0001）。我们还建立了高级别浆液性癌（HGSC）患者3年和5年生存的预测模型。由于HRD评分与肿瘤细胞分裂和复制密切相关，代表累积基因组疤痕的定量HRD评分在增殖的肿瘤细胞中动态增加。我们强调了HRD评分生物标志物在卵巢癌预后预测中的作用。
