DataSheet_1_Mutational Pattern in Multiple Pulmonary Nodules Are Associated With Early Stage Lung Adenocarcinoma.docx

The clinical significance of mutation in multiple pulmonary nodules is largely limited by single gene mutation-directed analysis and lack of validation of gene expression profiles. New analytic strategy is urgently needed for comprehensive understanding of genomic data in multiple pulmonary nodules. In this study, we performed whole exome sequencing in 16 multiple lung nodules and 5 adjacent normal tissues from 4 patients with multiple pulmonary nodules and decoded the mutation information from a perspective of cellular functions and signaling pathways. Mutated genes as well as mutation patterns shared in more than two lesions were identified and characterized. We found that the number of mutations or mutated genes and the extent of protein structural changes caused by different mutations is positively correlated with the degree of malignancy. Moreover, the mutated genes in the nodules are associated with the molecular functions or signaling pathways related to cell proliferation and survival. We showed a developing pattern of quantity (the number of mutations/mutated genes) and quality (the extent of protein structural changes) in multiple pulmonary nodules. The mutation and mutated genes in multiple pulmonary nodules are associated with cell proliferation and survival related signaling pathways. This study provides a new perspective for comprehension of genomic mutational data and might shed new light on deciphering molecular evolution of early stage lung adenocarcinoma.

本项研究旨在探究多发性肺结节中突变的意义，当前对此类突变的临床重要性多局限于针对单一基因突变的分析以及基因表达谱验证的不足。针对多发性肺结节基因组数据的全面理解，迫切需要新的分析策略。在本研究中，我们对来自4名多发性肺结节患者的16个肺结节及5个邻近的正常组织进行了全外显子测序，并从细胞功能和信号通路的角度对突变信息进行解码。识别并描述了突变基因及其在超过两个病灶中共享的突变模式。研究发现，突变数量或突变基因的数量以及由不同突变引起的蛋白质结构变化程度与恶性肿瘤的严重程度呈正相关。此外，结节中的突变基因与细胞增殖和存活相关的分子功能或信号通路相关。本研究揭示了多发性肺结节中突变数量（突变/突变基因数量）和质量（蛋白质结构变化程度）的发展模式。多发性肺结节中的突变和突变基因与细胞增殖和存活相关的信号通路相关。本研究为理解基因组突变数据提供了新的视角，并可能为揭示早期肺腺癌的分子演化提供新的启示。