Department of Pulmonology, Radboud University Medical Center, Postbox 9101, 6500 HB, Nijmegen, The Netherlands.
Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands.
Respir Res. 2021 Nov 24;22(1):302. doi: 10.1186/s12931-021-01871-0.
Lung cancer is the leading cause of cancer death worldwide. With the growing number of targeted therapies and the introduction of immuno-oncology (IO), personalized medicine has become standard of care in patients with metastatic disease. The development of predictive and prognostic biomarkers is of great importance. Mutational signatures harbor potential clinical value as predictors of therapy response in cancer. Here we set out to investigate particular mutational processes by assessing mutational signatures and associations with clinical features, tumor mutational burden (TMB) and targetable mutations.
In this retrospective study, we studied tumor DNA from patients with non-small cell lung cancer (NSCLC) irrespective of stage. The samples were sequenced using a 2 megabase (Mb) gene panel. On each sample TMB was determined and defined as the total number of single nucleotide mutations per Mb (mut/Mb) including non-synonymous mutations. Mutational signature profiling was performed on tumor samples in which at least 30 somatic single base substitutions (SBS) were detected.
In total 195 samples were sequenced. Median total TMB was 10.3 mut/Mb (range 0-109.3). Mutational signatures were evaluated in 76 tumor samples (39%; median TMB 15.2 mut/Mb). SBS signature 4 (SBS4), associated with tobacco smoking, was prominently present in 25 of 76 samples (33%). SBS2 and/or SBS13, both associated with activity of the AID/APOBEC family of cytidine deaminases, were observed in 11 of 76 samples (14%). SBS4 was significantly more present in early stages (I and II) versus advanced stages (III and IV; P = .005).
In a large proportion of NSCLC patients tissue panel sequencing with a 2 Mb panel can be used to determine the mutational signatures. In general, mutational signature SBS4 was more often found in early versus advanced stages of NSCLC. Further studies are needed to determine the clinical utility of mutational signature analyses.
肺癌是全球癌症死亡的主要原因。随着靶向治疗的数量不断增加和免疫肿瘤学（IO）的引入，个性化医学已成为转移性疾病患者的标准治疗方法。预测和预后生物标志物的发展非常重要。突变特征作为癌症治疗反应的预测因子具有潜在的临床价值。在这里，我们通过评估突变特征以及与临床特征、肿瘤突变负担（TMB）和可靶向突变的关联，来研究特定的突变过程。
在这项回顾性研究中，我们研究了不论分期如何的非小细胞肺癌（NSCLC）患者的肿瘤 DNA。使用 2 兆碱基（Mb）基因面板对样本进行测序。在每个样本中，均确定了 TMB，并定义为每 Mb 中包含非同义突变在内的总单核苷酸突变数（mut/Mb）。在至少检测到 30 个体细胞单碱基替换（SBS）的肿瘤样本中进行了突变特征分析。
共对 195 个样本进行了测序。中位总 TMB 为 10.3 mut/Mb（范围 0-109.3）。在 76 个肿瘤样本（39%；中位 TMB 15.2 mut/Mb）中评估了突变特征。与吸烟有关的 SBS4 突变特征在 25 个样本（33%）中明显存在。11 个样本（14%）中观察到 SBS2 和/或 SBS13，这两个特征均与 AID/APOBEC 家族胞嘧啶脱氨酶的活性有关。SBS4 在早期（I 和 II 期）与晚期（III 和 IV 期）相比，其存在更为显著（P = .005）。
在很大一部分 NSCLC 患者中，使用 2 Mb 面板的组织面板测序可用于确定突变特征。一般来说，SBS4 突变特征在 NSCLC 的早期阶段比晚期阶段更为常见。需要进一步研究来确定突变特征分析的临床效用。
