Department of Chemotherapy, Clinic of Oncology and Hematology, North Estonia Medical Centre, Tallinn, Estonia.
Department of Chemistry and Biotechnology, Tallinn University of Technology, Tallinn, Estonia.
Gene. 2023 Nov 15;885:147690. doi: 10.1016/j.gene.2023.147690. Epub 2023 Aug 5.
33-70% of lung cancer (LC) patients develop recurrence after radical treatment. Previous studies have shown the importance of clinical-pathological characteristics for the risk of recurrence. The role of molecular mechanisms remains unclear. The aim was analyzing genomic features in LC patients with local (LR) versus distant recurrence (DR) to predict the risk and type of recurrence.
Patients previously curatively treated with LC recurrences from 2015 to 2017 were retrospectively enrolled. Histological specimens collected at the time of LC diagnosis were sent for whole exome sequencing (WES). Genomic data was analyzed for single nucleotide polymorphisms (SNPs) and insertion-deletion mutations (INDELs).
191 patients were included. 33% of patients had LR and 67% DR, with median recurrence-free survival (RFS) 15.4 versus 11.2 months (p = 0.20) and overall survival (OS) after recurrence 12.9 versus 8.5 months (p = 0.007), respectively. Of various laboratory parameters studied, lymphocytes were significantly decreased at recurrence (p < 0.0001) in the DR group. In genetic analysis, significantly enriched INDEL mutations were found in 38 and 98 genes and SNP mutations in 63 and 179 genes in DR and LR groups, respectively. DMXL2 and ABCC9 gene mutations caused by INDELs appeared exclusively in the DR group. Enrichment analysis detected genes, like KNTC1, CLASP1, CLASP2 and CENPE, responsible of microtubule disturbance in the DR group. Furthermore, genes related to cytosolic Ca2+ such as STIM1, ITPR3 and RYR3, were significantly enriched in DR group whereas in LR group enrichment of pathways related to endoplasmic/sarcoplasmic reticulum Ca2+ was observed.
Our findings indicate distinct genomic signatures in the LR and DR cohorts, with microtubule disturbance and calcium regulation playing a crucial role in invasiveness in DR of LC. Understanding molecular mechanisms of LC recurrence may lead to the discovery of novel drug targets that could potentially stop spread of cancer cells.
33%-70%的肺癌（LC）患者在根治性治疗后会复发。先前的研究表明临床病理特征对复发风险很重要。但分子机制的作用仍不清楚。本研究旨在分析局部（LR）与远处复发（DR）的 LC 患者的基因组特征，以预测复发的风险和类型。
回顾性纳入 2015 年至 2017 年经根治性治疗后出现 LC 复发的患者。收集 LC 诊断时的组织标本进行全外显子组测序（WES）。对基因组数据进行单核苷酸多态性（SNP）和插入缺失突变（INDEL）分析。
共纳入 191 例患者。33%的患者发生 LR，67%的患者发生 DR，无复发生存期（RFS）分别为 15.4 个月和 11.2 个月（p=0.20），复发后总生存期（OS）分别为 12.9 个月和 8.5 个月（p=0.007）。在研究的各种实验室参数中，DR 组复发时淋巴细胞明显减少（p<0.0001）。在遗传分析中，DR 和 LR 组分别发现了 38 个和 98 个基因中明显富集的 INDEL 突变，63 个和 179 个基因中 SNP 突变。ABCC9 和 DMXL2 基因的 INDEL 突变仅在 DR 组中出现。富集分析检测到 KNTC1、CLASP1、CLASP2 和 CENPE 等基因，这些基因在 DR 组中与微管干扰有关。此外，STIM1、ITPR3 和 RYR3 等与细胞质 Ca2+相关的基因在 DR 组中明显富集，而在 LR 组中则观察到与内质网/肌浆网 Ca2+相关的途径富集。
我们的研究结果表明，LR 和 DR 队列存在不同的基因组特征，微管干扰和钙调节在 LC 的 DR 中侵袭性方面起着关键作用。了解 LC 复发的分子机制可能会发现新的药物靶点，从而阻止癌细胞的扩散。
