Department of Environmental and Occupational Health, School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA.
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan.
Int J Mol Sci. 2023 Jan 25;24(3):2382. doi: 10.3390/ijms24032382.
Tumor recurrence poses a significant challenge to the clinical management of stage I lung adenocarcinoma after curative surgical resection. Matrix metalloproteinases (MMPs) increase expression and correlate with recurrence and metastasis in surgically resected non-small cell lung cancer. However, the impact of MMPs on survival outcome varies, and their roles in patients with stage I lung adenocarcinoma remain unclear. In two discovery cohorts, we first analyzed 226 stage I-II lung adenocarcinoma cases in the GSE31210 cohort using a clustering-based method and identified a 150-gene MMP cluster with increased expression in tumors associated with worse survival outcomes. A similar analysis was performed on 517 lung adenocarcinoma cases in the Cancer Genome Atlas cohort. A 185-gene MMP cluster was identified, which also showed increased expression in tumors and correlated with poor survival outcomes. We further streamlined from the discovery cohorts a 36-gene MMP signature significantly associated with recurrence and worse overall survival in patients with stage I lung adenocarcinoma after surgical resection. After adjusting for covariates, the high MMP-gene signature expression remained an independent risk factor. In addition, the MMP-gene signature showed enrichment in epidermal growth factor receptor wild-type lung tumors, especially for those with Kirsten rat sarcoma virus mutations. Using an independent validation cohort, we further validated the MMP-gene signature in 70 stage I lung adenocarcinoma cases. In conclusion, MMP-gene signature is a potential predictive and prognostic biomarker to stratify patients with stage I lung adenocarcinoma into subgroups based on their risk of recurrence for aiding physicians in deciding the personalized adjuvant therapeutics.
肿瘤复发是 I 期肺腺癌患者根治性手术后临床管理的重大挑战。基质金属蛋白酶（MMPs）在非小细胞肺癌手术切除标本中的表达增加，并与复发和转移相关。然而，MMPs 对生存结局的影响是可变的，它们在 I 期肺腺癌患者中的作用尚不清楚。在两个探索性队列中，我们首先使用基于聚类的方法分析了 GSE31210 队列中的 226 例 I-II 期肺腺癌病例，鉴定出一个 MMP 基因簇，其在与较差生存结局相关的肿瘤中表达增加。在癌症基因组图谱队列中的 517 例肺腺癌病例中进行了类似的分析。鉴定出一个 185 个基因 MMP 基因簇，该基因簇在肿瘤中的表达也增加，并与不良生存结局相关。我们进一步从发现队列中简化出一个 MMP 基因签名，该签名与手术切除后 I 期肺腺癌患者的复发和总体生存较差显著相关。在调整协变量后，高 MMP 基因签名表达仍然是一个独立的危险因素。此外，MMP 基因签名在表皮生长因子受体野生型肺肿瘤中富集，尤其是在具有 Kirsten 大鼠肉瘤病毒突变的肿瘤中。使用独立的验证队列，我们在 70 例 I 期肺腺癌病例中进一步验证了 MMP 基因签名。总之，MMP 基因签名是一种潜在的预测和预后生物标志物，可以根据患者的复发风险将 I 期肺腺癌患者分为亚组，以帮助医生决定个体化辅助治疗。
