DataSheet_2_Glioblastoma Primary Cells Retain the Most Copy Number Alterations That Predict Poor Survival in Glioma Patients.pdf

Gliomas are solid tumors that originate from glial cells in the brain or spine and account for 74.6% of malignant primary central nervous system tumors worldwide. As patient-derived primary cells are important tools for drug screening and new therapy development in glioma, we aim to understand the genomic similarity of the primary cells to their parental tumors by comparing their whole-genome copy number variations and expression profile of glioma clinicopathologic factors. We found that the primary cells from grade II/III gliomas lost most of the gene copy number alterations (CNAs), which were mainly located on chromosome 1p and 19q in their parental tumors. The glioblastoma (GBM) primary cells preserved 83.7% of the gene CNAs in the parental GBM tumors, including chromosome 7 gain and 10q loss. The CNA gains of LINC00226 and ADAM6 and the chromosome 16p11 loss were reconstituted in primary cells from both grade II/III gliomas and GBMs. Interestingly, we found these CNAs were correlated to overall survival (OS) in glioma patients using the Merged Cohort LGG and GBM dataset from cBioPortal. The gene CNAs preserved in glioma primary cells often predicted poor survival, whereas the gene CNAs lost in grade II/III primary cells were mainly associated to better prognosis in glioma patients. Glioma prognostic factors that predict better survival, such as IDH mutations and 1p/19q codeletion in grade II/III gliomas, were lost in their primary cells, whereas methylated MGMT promoters as well as TERT promoter mutations were preserved in GBM primary cells while lost in grade II/III primary cells. Our results suggest that GBM primary cells tend to preserve CNAs in their parental tumors, and these CNAs are correlated to poor OS and predict worse prognosis in glioma patients.

胶质瘤(Gliomas)是起源于脑或脊髓胶质细胞的实体瘤，在全球恶性原发性中枢神经系统肿瘤中占比达74.6%。由于患者来源原代细胞是胶质瘤药物筛选与新型治疗手段开发的重要工具，本研究旨在通过比较全基因组拷贝数变异与胶质瘤临床病理因素的表达谱，解析原代细胞与其亲本肿瘤的基因组相似性。研究发现，源自Ⅱ/Ⅲ级胶质瘤的原代细胞丢失了其亲本肿瘤中主要位于1号染色体短臂（1p）与19号染色体长臂（19q）的绝大多数基因拷贝数变异(CNAs)。而胶质母细胞瘤(GBM)原代细胞则保留了亲本胶质母细胞瘤中83.7%的基因拷贝数变异，包括7号染色体拷贝数增加与10号染色体长臂缺失。Ⅱ/Ⅲ级胶质瘤与胶质母细胞瘤来源的原代细胞均重现了LINC00226、ADAM6的拷贝数增加以及16号染色体p11区域缺失这一变异特征。有趣的是，借助cBioPortal平台的合并队列低级别胶质瘤(LGG)与胶质母细胞瘤(GBM)数据集，本研究发现上述拷贝数变异与胶质瘤患者的总生存期(OS)相关：保留于胶质瘤原代细胞中的基因拷贝数变异往往预示不良生存结局，而在Ⅱ/Ⅲ级胶质瘤原代细胞中丢失的基因拷贝数变异则主要与胶质瘤患者更好的预后相关。诸如Ⅱ/Ⅲ级胶质瘤中的异柠檬酸脱氢酶(IDH)突变与1p/19q共缺失这类可预测更佳生存的胶质瘤预后因子，在其原代细胞中均已丢失；而MGMT启动子甲基化与端粒酶逆转录酶(TERT)启动子突变则在胶质母细胞瘤原代细胞中得以保留，但在Ⅱ/Ⅲ级胶质瘤原代细胞中丢失。本研究结果表明，胶质母细胞瘤原代细胞倾向于保留其亲本肿瘤的拷贝数变异，且此类变异与较差的总生存期相关，可预测胶质瘤患者更不良的预后。