全外显子组测序和肺腺癌 microRNA 谱分析确定了 I 期及其亚期肿瘤的风险预测特征。

Whole exome sequencing and MicroRNA profiling of lung adenocarcinoma identified risk prediction features for tumors at stage I and its substages.

机构信息

Institute of Statistical Science, Academia Sinica, Taipei, Taiwan.

Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan; Centers of Genomic and Precision Medicine, National Taiwan University, Taipei, Taiwan; Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan; Institute of Medical Device and Imaging, College of Medicine, National Taiwan University, Taipei, Taiwan; Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taipei, Taiwan; Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.

出版信息

Lung Cancer. 2023 Oct;184:107352. doi: 10.1016/j.lungcan.2023.107352. Epub 2023 Aug 20.

DOI:10.1016/j.lungcan.2023.107352

PMID:37657238

Abstract

OBJECTIVES

About 20% of stage I lung adenocarcinoma (LUAD) patients suffer a relapse after surgical resection. While finer substages have been defined and refined in the AJCC staging system, clinical investigations on the tumor molecular landscape are lacking.

MATERIALS AND METHODS

We performed whole exome sequencing, DNA copy number and microRNA profiling on paired tumor-normal samples from a cohort of 113 treatment-naïve stage I Taiwanese LUAD patients. We searched for molecular features associated with relapse-free survival (RFS) of stage I or its substages and validated the findings with an independent Caucasian LUAD cohort.

RESULTS

We found sixteen nonsynonymous mutations harbored at EGFR, KRAS, TP53, CTNNB1 and six other genes associated with poor RFS in a dose-dependent manner via variant allele fraction (VAF). An index, maxVAF, was constructed to quantify the overall mutation load from genes other than EGFR. High maxVAF scores discriminated a small group of high-risk LUAD at stage I (median RFS: 4.5 versus 69.5 months; HR = 10.5, 95% CI = 4.22-26.12, P < 0.001). At the substage level, higher risk was found for patients with high maxVAF or high miR-31; IA (median RFS: 32.1 versus 122.8 months, P = 0.005) and IB (median RFS: 7.1 versus 26.2, P = 0.049). MicroRNAs, miR-182, miR-183 and miR-196a were found correlated with EGFR mutation and poor RFS in stage IB patients.

CONCLUSION

Distinctive features of somatic gene mutation and microRNA expression of stage I LUAD are characterized to complement the survival prognosis by substaging. The findings open up more options for precision management of stage I LUAD patients.

摘要

目的

约 20%的 I 期肺腺癌（LUAD）患者在手术后复发。虽然 AJCC 分期系统已经定义和细化了更精细的亚分期，但对肿瘤分子特征的临床研究仍很缺乏。

材料和方法

我们对 113 例未经治疗的台湾 I 期 LUAD 患者的配对肿瘤-正常样本进行了全外显子测序、DNA 拷贝数和 microRNA 谱分析。我们寻找与 I 期或其亚分期无复发生存（RFS）相关的分子特征，并通过独立的高加索 LUAD 队列进行了验证。

结果

我们发现，16 个非同义突变位于 EGFR、KRAS、TP53、CTNNB1 和另外 6 个基因中，这些突变与通过变异等位基因分数（VAF）呈剂量依赖性的不良 RFS 相关。构建了一个指数 maxVAF，用于量化除 EGFR 以外的基因的总体突变负荷。高 maxVAF 评分可区分一小部分 I 期高危 LUAD（中位 RFS：4.5 与 69.5 个月；HR=10.5，95%CI=4.22-26.12，P<0.001）。在亚分期水平上，高 maxVAF 或高 miR-31 的患者风险更高；IA 期（中位 RFS：32.1 与 122.8 个月，P=0.005）和 IB 期（中位 RFS：7.1 与 26.2，P=0.049）。miR-182、miR-183 和 miR-196a 与 IB 期患者的 EGFR 突变和不良 RFS 相关。