INTRODUCTION Studies have yet to characterize the differences in molecular profiles of lung adenocarcinoma (LUAD) among divergent ethnic groups. Herein, we conducted comprehensive molecular profiling of LUAD in never or light smokers from Asia in order to discover novel targetable mutations and prognostic biomarkers of this distinct disease entity. METHODS We analyzed 996 cases of Japanese LUAD, and performed whole-exome sequencing and/or RNA-seq in 125 cases of Japanese LUAD negative for the driver oncogenes defined by conventional laboratory testing. We also investigated the clinical and pathological characteristics among the 996 cases. RESULTS Driver oncogenes were identified in 88 cases (70.4%) with specific hotspot mutations differing from those in The Cancer Genome Atlas (TCGA) study. Two actionable novel fusions of FGFR2 and NRG2α were also identified. Clustering based on mRNA expression profiles, but not genetic mutational ones, could predict patient prognosis. The risk score generated by the expression of a three-gene set was a strong prognostic marker for overall survival and progression-free survival in our cohort, and was further validated using TCGA cohort. Among the 996 cases, each driver alteration is distributed across all histological subtypes. Adenocarcinoma in situ was identified to harbor driver mutations, suggesting that these alterations are early events in the pathogenesis of LUAD. ERBB2 mutations were over-represented in young adults. CONCLUSION This study indicates the value of applying gene expression profiling for predicting the prognosis after a surgical operation, and that the identification of actionable mutations is important for optimizing targeted drugs in Japanese LUAD.

中文翻译：

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从日本从不吸烟或轻度吸烟者肺腺癌的综合分析中鉴定新型 CD74-NRG2α 融合

介绍 研究尚未表征不同种族群体中肺腺癌 (LUAD) 分子谱的差异。在此，我们对来自亚洲的从不吸烟或轻度吸烟者进行了 LUAD 的全面分子分析，以发现这种独特疾病实体的新型可靶向突变和预后生物标志物。方法我们分析了 996 例日本 LUAD，并对 125 例日本 LUAD 阴性的日本 LUAD 进行了全外显子组测序和/或 RNA-seq，这些患者通过常规实验室检测确定的驱动癌基因为阴性。我们还调查了 996 例患者的临床和病理特征。结果 在 88 例 (70.4%) 中发现了驱动致癌基因，这些病例具有与癌症基因组图谱 (TCGA) 研究不同的特定热点突变。还鉴定了 FGFR2 和 NRG2α 的两种可操作的新型融合。基于 mRNA 表达谱而非基因突变谱的聚类可以预测患者的预后。三基因组表达产生的风险评分是我们队列中总生存期和无进展生存期的强预后标志物，并使用 TCGA 队列进一步验证。在 996 个病例中，每个驱动程序改变分布在所有组织学亚型中。原位腺癌被鉴定为含有驱动突变，表明这些改变是 LUAD 发病机制中的早期事件。ERBB2 突变在年轻人中过多。结论 本研究表明应用基因表达谱预测外科手术后预后的价值，