The prognostic effect of single and multiple cancer-related somatic mutations in resected non-small-cell lung cancer
The prognostic effect of single and multiple cancer-related somatic mutations in resected non-small-cell lung cancer
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DOI：
10.1016/j.lungcan.2018.06.023
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发表时间：
2018-09-01
期刊：
影响因子：
5.3
通讯作者：
Shepherd, Frances A.
中科院分区：
文献类型：
--
作者：
Jao, Kevin;Tomasini, Pascale;Shepherd, Frances A.
简介：体细胞突变正成为非小细胞肺癌 (NSCLC) 患者治疗选择和结果越来越重要的生物标志物。多种体细胞突变在早期 NSCLC 中的作用尚不清楚。方法：通过 Mi-SEQ 或 Sequenom 多重平台进行下一代测序，对玛格丽特公主癌症中心 214 例切除的 NSCLC 患者的组织进行分析。研究了突变状态、基线患者特征和结果（手术切除后的无病生存期 (DFS) 和总生存期 (OS)）之间的关联。 结果：在 184 名切除的 I-III 期 NSCLC 患者中鉴定出体细胞突变：无 (n = 30)、单发 (n = 101) 和多发 (>= 2，n = 83)。多种突变与年轻（p = 0.0006）、女性（p = 0.012）、吸烟状况（p = 0.002）和腺癌组织学（p = 0.0001）显着相关。 TP53、KRAS 和 EGFR 是最常见的突变。 TP53 突变是最常见的共突变，发生在 72% 的多突变患者中。在单变量分析中，在切除的 I-III 期患者中，多种突变与较差的 DFS 显着相关（HR = 2.56，p = 0.003），但与 OS 无关。携带 KRAS 和 EGFR 突变的患者也与较短的 DFS 相关（分别为 HR = 2.52，p = 0.016 和 HR = 4.37，p = 0.001），但 OS 没有差异。 TP53 突变与较短的 DFS（HR = 2.21，p = 0.02）和较短的 OS（HR = 3.08，p = 0.02）相关。在亚组单变量分析中，I期疾病患者较差的DFS与多种突变（p = 0.0015）、EGFR（HR = 3.14，p = 0.006）和TP53（HR = 2.46，p = 0.018）相关。结论：已知体细胞突变的存在与切除的NSCLC中较差的DFS相关。这些差异既具有统计学意义，又具有临床相关性。 EGFR、KRAS 和 TP53 突变的存在也与不良后果相关。需要更大的数据集来验证突变状态是否是早期 NSCLC 的独立预后因素。
Introduction: Somatic mutations are becoming increasingly important biomarkers for treatment selection and outcome in patients with non-small-cell lung cancer (NSCLC). The role of multiple somatic mutations in early-stage NSCLC is unclear.Methods: Tissue from 214 patients with resected NSCLC at the Princess Margaret Cancer Centre was analyzed by next-generation sequencing by Mi-SEQ or Sequenom multiplex platforms. Associations between mutation status, baseline patient characteristics and outcomes (disease-free survival (DFS) after surgical resection and overall survival (OS)) were investigated.Results: Somatic mutations were identified in 184 patients with resected stage I-Ill NSCLC: None (n = 30), single (n = 101) and multiple (>= 2, n = 83). Multiple mutations were significantly associated with younger age (p = 0.0006), female sex (p = 0.012), smoking status (p = 0.002) and adenocarcinoma histology (p = 0.0001). TP53, KRAS and EGFR were the most common mutations. TP53 mutation was the most frequent co-mutation occurring in 72% of patients with multiple mutations. In resected stage I-III patients, multiple mutations were significantly associated with worse DFS (HR = 2.56, p = 0.003) but not OS on univariate analysis. Patients with KRAS and EGFR mutations were also associated with shorter DFS (HR = 2.52, p = 0.016 and HR = 4.37, p = 0.001 respectively) but no OS difference. TP53 mutation was associated with both shorter DFS (HR = 2.21, p = 0.02) and OS (HR = 3.08, p = 0.02). In subgroup univariate analysis, poorer DFS was associated with multiple mutations (p = 0.0015), EGFR (HR = 3.14, p = 0.006), and TP53 (HR = 2.46, p = 0.018) in patients with stage I disease.Conclusion: The presence of known somatic mutations is associated with worse DFS in resected NSCLC. The differences are both statistically significant and clinically relevant. The presence of EGFR, KRAS and TP53 mutations was also associated with adverse outcomes. Larger datasets are required to validate whether mutational status is an independent prognostic factor in early stage NSCLC.