Yu Guangyang, Pang Ying, Merchant Mythili, Kesserwan Chimene, Gangalapudi Vineela, Abdelmaksoud Abdalla, Ranjan Alice, Kim Olga, Wei Jun S, Chou Hsien-Chao, Wen Xinyu, Sindiri Sivasish, Song Young K, Xi Liqiang, Kaplan Rosandra N, Armstrong Terri S, Gilbert Mark R, Aldape Kenneth, Khan Javed, Wu Jing
Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Cancers (Basel). 2021 Dec 3;13(23):6092. doi: 10.3390/cancers13236092.
A consistent correlation between tumor mutation burden (TMB) and tumor immune microenvironment has not been observed in gliomas as in other cancers.
Driver germline and somatic mutations, TMB, neoantigen, and immune cell signatures were analyzed using whole exome sequencing (WES) and transcriptome sequencing of tumor and WES of matched germline DNA in a cohort of 66 glioma samples (44 IDH-mutant and 22 IDH-wildtype).
Fourteen samples revealed a hypermutator phenotype (HMP). Eight pathogenic (P) or likely pathogenic (LP) germline variants were detected in 9 (19%) patients. Six of these 8 genes were DNA damage repair genes. P/LP germline variants were found in 22% of IDH-mutant gliomas and 12.5% of IDH-wildtype gliomas ( = 0.7). TMB was correlated with expressed neoantigen but showed an inverse correlation with immune score (R = -0.46, = 0.03) in IDH-wildtype tumors and no correlation in IDH-mutant tumors. The Antigen Processing and Presentation (APP) score correlated with immune score and was surprisingly higher in NHMP versus HMP samples in IDH-wildtype gliomas, but higher in HMP versus NHMP in IDH-mutant gliomas.
TMB was inversely correlated with immune score in IDH-wildtype gliomas and showed no correlation in IDH-mutant tumors. APP was correlated with immune score and may be further investigated as a biomarker for response to immunotherapy in gliomas. Studies of germline variants in a larger glioma cohort are warranted.
与其他癌症不同，在胶质瘤中尚未观察到肿瘤突变负荷（TMB）与肿瘤免疫微环境之间存在一致的相关性。
在一组66例胶质瘤样本（44例异柠檬酸脱氢酶（IDH）突变型和22例IDH野生型）中，使用全外显子组测序（WES）、肿瘤转录组测序以及匹配的种系DNA的WES，分析驱动种系和体细胞突变、TMB、新抗原和免疫细胞特征。
14个样本显示出高突变体表型（HMP）。在9例（19%）患者中检测到8个致病（P）或可能致病（LP）的种系变异。这8个基因中的6个是DNA损伤修复基因。在22%的IDH突变型胶质瘤和12.5%的IDH野生型胶质瘤中发现了P/LP种系变异（P = 0.7）。在IDH野生型肿瘤中，TMB与表达的新抗原相关，但与免疫评分呈负相关（R = -0.46，P = 0.03），而在IDH突变型肿瘤中无相关性。抗原加工与呈递（APP）评分与免疫评分相关，令人惊讶的是，在IDH野生型胶质瘤中，非高突变体表型（NHMP）样本的APP评分高于HMP样本，但在IDH突变型胶质瘤中，HMP样本的APP评分高于NHMP样本。
在IDH野生型胶质瘤中，TMB与免疫评分呈负相关，而在IDH突变型肿瘤中无相关性。APP与免疫评分相关，可能作为胶质瘤免疫治疗反应的生物标志物进行进一步研究。有必要在更大的胶质瘤队列中研究种系变异。
