奥拉帕尼
下调和上调
塞鲁美替尼
人口
免疫检查点
癌症研究
转录组
生物
医学
免疫学
免疫系统
突变
免疫疗法
遗传学
基因表达
聚ADP核糖聚合酶
基因
聚合酶
环境卫生
克拉斯
作者
Tingting Chen,Tong Yu,Shuping Zhuang,Yiding Geng,Junwen Xue,Jiayi Wang,Liqiang Ai,Bin Chen,Zhangxiang Zhao,Yawei Li,Jinghao Wang,Haihai Liang,Yan Xu,Yunyan Gu
标识
DOI:10.1038/s41416-022-01836-0
摘要
Mutations in BRCA1 or BRCA2 (BRCA1/2) cause homologous recombination deficiency (HRD). Ovarian cancer (OvCa) patients harbouring HRD beyond BRCA1/2 mutation result in a state referred to as "BRCAness". OvCa with BRCAness could benefit from PARP inhibitors. This study aims to identify a signature to detect the BRCAness population at the transcriptome level.We used a rank-based algorithm to develop a qualitative BRCAness signature for OvCa. Upregulation of CXCL1 with downregulation of SV2A and upregulation of LY9 with downregulation of CHRNB3 were constructed as the BRCAness signature (2 gene pairs, 2-GPS) for OvCa.OvCa samples that were classified as BRCAness by 2-GPS showed improved overall survival, progression-free survival and exhibited increased multi-omics alterations in homologous recombination genes and enhanced sensitivity to immune checkpoint blockade. BRCAness cells were sensitive to PARP inhibitors. By biological experiments, we validated SKOV3 cells and patients with HRD exhibited higher expression of CXCL1 than SV2A and higher expression of LY9 than CHRNB3 at mRNA level. Both SKOV3 and A2780 with HRD were sensitive to mitomycin C, cisplatin and olaparib.In conclusion, 2-GPS could robustly predict BRCAness OvCa at the individual level and extend the population who may benefit from PARP inhibitors.
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