Amuzu Setor, Carmona Euridice, Mes-Masson Anne-Marie, Greenwood Celia M T, Tonin Patricia N, Ragoussis Jiannis
Department of Human Genetics, McGill University, Montreal, QC H3A 0C7, Canada.
McGill Genome Centre, McGill University, Montreal, QC H3A 0G1, Canada.
Cancers (Basel). 2021 Mar 15;13(6):1296. doi: 10.3390/cancers13061296.
The benefit of PARP inhibitor olaparib in relapsed and advanced high-grade serous ovarian carcinoma (HGSOC) is well established especially in mutation carriers. Identification of additional biomarkers can help expand the population of patients most likely to benefit from olaparib treatment. To identify candidate markers of olaparib response we analyzed genomic and in vitro olaparib response data from two independent groups of cancer cell lines. Using pan-cancer cell lines ( = 896) from the Genomics of Drug Sensitivity in Cancer database, we applied linear regression methods to identify statistically significant gene predictors of olaparib response based on mRNA expression. We then analyzed whole exome sequencing and mRNA gene expression data from our collection of 18 HGSOC cell lines previously classified as sensitive, intermediate, or resistant based on in vitro olaparib response for mutations, copy number variation and differential expression of candidate olaparib response genes. We identify genes previously associated with olaparib response (, ), and discover novel candidate olaparib sensitivity genes with known functions including interaction with PARP1 (, ) and involvement in homologous recombination DNA repair (). Further investigations at experimental and clinical levels are required to validate novel candidates, and ultimately determine their efficacy as potential biomarkers of olaparib sensitivity.
聚（ADP - 核糖）聚合酶（PARP）抑制剂奥拉帕利在复发性和晚期高级别浆液性卵巢癌（HGSOC）中的益处已得到充分证实，尤其是在特定基因突变携带者中。识别其他生物标志物有助于扩大最有可能从奥拉帕利治疗中获益的患者群体。为了识别奥拉帕利反应的候选标志物，我们分析了来自两组独立癌细胞系的基因组数据和体外奥拉帕利反应数据。利用癌症药物敏感性基因组学数据库中的泛癌细胞系（n = 896），我们应用线性回归方法，基于mRNA表达来识别奥拉帕利反应的统计学显著基因预测因子。然后，我们分析了我们收集的18个HGSOC细胞系的全外显子组测序和mRNA基因表达数据，这些细胞系先前根据体外奥拉帕利反应被分类为敏感、中等或耐药，以研究候选奥拉帕利反应基因的突变、拷贝数变异和差异表达情况。我们鉴定出了先前与奥拉帕利反应相关的基因（如……），并发现了具有已知功能的新型奥拉帕利敏感性基因，包括与PARP1相互作用（如……）以及参与同源重组DNA修复（如……）。需要在实验和临床水平上进行进一步研究，以验证新型候选基因，并最终确定它们作为奥拉帕利敏感性潜在生物标志物的功效。
