对肺腺癌进行全外显子组测序和微小RNA分析，识别出了一些能够预测I期和其亚期肿瘤风险的特征。
Whole exome sequencing and MicroRNA profiling of lung adenocarcinoma identified risk prediction features for tumors at stage I and its substages.
发表日期：2023 Aug 20
作者：
Hao Ho, Sung-Liang Yu, Hsuan-Yu Chen, Shin-Sheng Yuan, Kang-Yi Su, Yi-Chiung Hsu, Chung-Ping Hsu, Cheng-Yen Chuang, Ya-Hsuan Chang, Yu-Cheng Li, Chiou-Ling Cheng, Gee-Chen Chang, Pan-Chyr Yang, Ker-Chau Li
来源：
LUNG CANCER
摘要：
大约20%的I期肺腺癌（LUAD）患者在手术切除后会复发。虽然AJCC分期系统中已对细分期进行了定义和改进，但对肿瘤分子景观的临床研究尚缺乏。我们对113例台湾I期LUAD患者进行了整个外显子测序、DNA拷贝数和microRNA分析。我们寻找与I期或其细分期复发无关的分子特征，并用独立的高加索人LUAD队列验证了这些发现。我们发现，通过变异等位基因比例（VAF），与较差的无复发生存期（RFS）相关的发生在EGFR、KRAS、TP53、CTNNB1和其他六种基因中的十六种非同义突变呈剂量依赖性。我们构建了一个指标maxVAF来量化除EGFR以外的基因的总突变负荷。高maxVAF得分可将少数高风险I期LUAD患者区分出来（中位RFS：4.5个月对比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与IA（中位RFS：32.1个月对比122.8个月，P = 0.005）和IB（中位RFS：7.1个月对比26.2个月，P = 0.049）患者的风险较高。我们发现，microRNA miR-182、miR-183和miR-196a与EGFR突变和IB期患者较差的RFS相关。细分期I LUAD的突变体基因和microRNA表达的独特特征被用来补充预后。这些发现为I期LUAD患者的精准治疗提供了更多选择。版权© 2023 Elsevier B.V. 保留所有权利。
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.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.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.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.Copyright © 2023 Elsevier B.V. All rights reserved.