Department of Systems Biology, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang, China.
Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang, China.
Br J Cancer. 2022 Sep;127(5):916-926. doi: 10.1038/s41416-022-01836-0. Epub 2022 May 26.
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.
BRCA1 或 BRCA2（BRCA1/2）的突变导致同源重组缺陷（HRD）。携带 HRD 的卵巢癌（OvCa）患者除了 BRCA1/2 突变外，还会导致一种被称为“BRCA 样状态”的状态。具有 BRCA 样状态的 OvCa 可能受益于 PARP 抑制剂。本研究旨在从转录组水平确定一种检测 BRCA 样状态人群的特征。
我们使用基于排名的算法开发了一种定性的 BRCA 样 OvCa 特征。上调 CXCL1，下调 SV2A，上调 LY9，下调 CHRNB3 构建了 BRCA 样特征（2 个基因对，2-GPS）用于 OvCa。
通过 2-GPS 分类为 BRCA 样的 OvCa 样本显示出改善的总生存期、无进展生存期，并表现出同源重组基因的多组学改变增加，以及对免疫检查点阻断的敏感性增强。BRCA 样细胞对 PARP 抑制剂敏感。通过生物学实验，我们验证了 HRD 的 SKOV3 细胞和患者的 CXCL1 在 mRNA 水平上的表达高于 SV2A，而 LY9 的表达高于 CHRNB3。具有 HRD 的 SKOV3 和 A2780 对丝裂霉素 C、顺铂和奥拉帕利均敏感。
总之，2-GPS 可以在个体水平上稳健地预测 BRCA 样 OvCa，并扩展可能受益于 PARP 抑制剂的人群。
