Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Department of Oncology, Affiliated Hospital of Qinghai University, Xining, China.
J Immunother Cancer. 2019 Jul 26;7(1):198. doi: 10.1186/s40425-019-0660-7.
To profile genomic and epigenomic of a naïve Chinese non-small cell lung cancer (NSCLC) cohort and investigate the association between tumor mutation burden (TMB) and DNA methylation (DNAm) to explore potential alternative/complimentary biomarkers for NSCLC immunotherapies.
A total of 89 tumor tissues with matched normal tissues from Chinese NSCLC patients were collected and subjected to whole exome sequencing (WES). From comparison, each patient was evaluated for the TMB value and divided into high, medium and low TMB based on TMB tertile distribution and then relatively high and low TMB samples were selected and subjected to DNAm profiling.
Patients in the low (n = 30), medium (n = 29), and high (n = 30) TMB tertiles had 1.1-2.5, 2.5-4.1, and 4.2-13.9 mutations/Mb, respectively. A statistical directly association between differential methylation probes (DMPs) and TMB level was observed in our cohort (r = 0.63, P value =0.0003) and this was confirmed by using TCGA NSCLC dataset (r = 0.43, P value =0.006). Relatively high TMB group (n = 16, 7.5-13.9 mutations/Mb) harbors more differential DMPs while less in relatively low TMB group (n = 13, 1.1-2.4 mutations/Mb). Eight hundred fifty-eight differential methylation regions (DMRs) were found in relatively high TMB group. In addition, 437 genes show DNAm aberrance status in high TMB patient group and 99 have been reported as its association with lung cancer.
To our knowledge, this is the first report for direct link between the methylome alterations and TMB in NSCLCs. High TMB NSCLCs had more DNAm aberrance and copy number variations (CNVs). In addition, the TMB distribution of Chinese NSCLCs population is lower than that of TCGA.
对一个中国非小细胞肺癌（NSCLC）患者的基因组和表观基因组进行分析，探讨肿瘤突变负担（TMB）与 DNA 甲基化（DNAm）之间的关联，以探索 NSCLC 免疫治疗的潜在替代/补充生物标志物。
收集了 89 例中国 NSCLC 患者的肿瘤组织及其配对的正常组织，进行全外显子测序（WES）。通过比较，根据 TMB 三分位分布评估每位患者的 TMB 值，并分为高、中、低 TMB 组，然后选择相对高、低 TMB 样本进行 DNAm 分析。
低 TMB 组（n=30）、中 TMB 组（n=29）和高 TMB 组（n=30）的 TMB 三分位值分别为 1.1-2.5、2.5-4.1 和 4.2-13.9 个突变/Mb。我们的队列中观察到差异甲基化探针（DMPs）与 TMB 水平之间存在统计学上的直接关联（r=0.63，P 值=0.0003），这一结果在 TCGA NSCLC 数据集（r=0.43，P 值=0.006）中得到了验证。相对高 TMB 组（n=16，7.5-13.9 个突变/Mb）的差异 DMP 较多，而相对低 TMB 组（n=13，1.1-2.4 个突变/Mb）的差异 DMP 较少。在相对高 TMB 组中发现了 858 个差异甲基化区域（DMRs）。此外，在高 TMB 患者组中，有 437 个基因显示 DNAm 异常状态，其中 99 个基因与肺癌有关。
据我们所知，这是首次报道 NSCLC 中甲基组改变与 TMB 之间的直接联系。高 TMB 的 NSCLC 有更多的 DNAm 异常和拷贝数变异（CNVs）。此外，中国 NSCLC 人群的 TMB 分布低于 TCGA。
