Department of Head and Neck/Thoracic Medical Oncology, the First People's Hospital of Foshan, Foshan, China.
Eur Rev Med Pharmacol Sci. 2020 Jul;24(14):7664-7672. doi: 10.26355/eurrev_202007_22267.
This study aimed to investigate the impact of tumor mutational burden (TMB) and DNA damage repair (DDR) gene alteration on overall survival (OS) in advanced non-small cell lung cancer (NSCLC) patients.
A DNA library of cancer cells from 67 NSCLC patients in stages III-IV was constructed for next-generation sequencing (NGS). Geneseeq422 probes were used for hybridization enrichment. The target-enriched library was sequenced on HiSeqNGS platforms, and we analyzed the relevant signaling pathways. Then, we correlated the OS of the patients with TMB and DDR mutations.
Many significant alterations were found, including in the EGFR, p53, KRAS, RB1, ERBB2, NF1, DNMT3A, ALK, MYC, PIK3CA, ROS1, BRAF, ARID1A, PTEN, CDKN2A, and FGF19 genes. We also identified many mutations in the genes relevant to the DDR pathway. Interestingly, we found that the TMB of patients with DDR gene mutations was dramatically higher than that in the DDR wild-type (WT). Univariable analysis showed that DNMT3A, RB1, DDR pathway-related gene mutations, and TMB were critical factors for the effects on OS. Multivariable analysis confirmed that DNMT3A and mutations in the DDR pathway-related genes were important for predicting OS.
Multiple mutations in the genes of the DDR pathway caused higher TMB levels, which resulted in longer OS. By contrast, OS was significantly longer in patients with non-DNMT3A mutations than in those with DNMT3A variants. DNMT3A alteration in NSCLC patients led to poor outcomes.
本研究旨在探讨肿瘤突变负担（TMB）和 DNA 损伤修复（DDR）基因改变对晚期非小细胞肺癌（NSCLC）患者总生存期（OS）的影响。
对 67 例 III-IV 期 NSCLC 患者的癌细胞构建了下一代测序（NGS）的 DNA 文库。使用 Geneseeq422 探针进行杂交富集。将目标富集文库在 HiSeqNGS 平台上进行测序，并分析相关信号通路。然后，我们将患者的 OS 与 TMB 和 DDR 突变相关联。
发现了许多显著的改变，包括 EGFR、p53、KRAS、RB1、ERBB2、NF1、DNMT3A、ALK、MYC、PIK3CA、ROS1、BRAF、ARID1A、PTEN、CDKN2A 和 FGF19 基因。我们还鉴定了许多与 DDR 通路相关的基因中的突变。有趣的是，我们发现 DDR 基因突变患者的 TMB 明显高于 DDR 野生型（WT）。单变量分析表明，DNMT3A、RB1、DDR 通路相关基因突变和 TMB 是影响 OS 的关键因素。多变量分析证实，DNMT3A 和 DDR 通路相关基因的突变是预测 OS 的重要因素。
DDR 通路基因的多种突变导致更高的 TMB 水平，从而导致更长的 OS。相比之下，非 DNMT3A 突变患者的 OS 明显长于 DNMT3A 变异患者。NSCLC 患者的 DNMT3A 改变导致不良结局。
