Introduction: Lung adenocarcinoma (ADC) with synchronous ground‐glass/lepidic (GG/L) nodules is considered a distinct disease entity in multiple synchronous lung cancers. Few studies have performed next‐generation sequencing analysis of these synchronous sequential lesions, and genetic alterations of GG/L nodules must be further investigated. Methods: We performed targeted sequencing in ADC with synchronous atypical adenomatous hyperplasia (AAH), ADC in situ, or minimally invasive ADC from 16 patients. Next‐generation sequencing was performed by using a customized panel including 154 cancer‐associated genes. Results: Multiple synchronous lesions in the same patient showed different mutation profiles, and some shared identically mutated genes. In five patients harboring EGFR‐mutant ADC, their synchronous GG/L nodules had EGFR mutation; however, none was observed in EGFR wild‐type ADC. The average numbers of exonic mutations were 4.2, 5.4, 4.0, and 5.4 in AAH, ADC in situ, minimally invasive ADC, and ADC, respectively. In each lesion type, various mutations, including LDL receptor related protein 1B gene (LRP1B), KRAS, EGFR, and BRAF were observed in AAH, and EGFR mutations were the most frequently observed in ADC. In all, 80% of mutations with a variant allele frequency of 20% or higher, which contained driver gene mutations, were identified in ADC. Intratumoral heterogeneity of the genetic profile was found between the lepidic and invasive areas of ADC, but the driver gene mutations were similar. Conclusions: This study suggests that ADC and synchronous GG/L nodules are genetically independent tumors. Intratumoral genetic heterogeneity of ADC was present, but driver gene mutations were homogeneously distributed. Driver gene mutations with a high variant allele frequency were identified in the invasive tumor. These findings support the relevance of molecular characterization of lung ADC and synchronous GG/L nodules.

中文翻译：

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多发同步磨玻璃/鳞状结节肺腺癌的靶向测序分析

简介：具有同步磨玻璃/贴壁样 (GG/L) 结节的肺腺癌 (ADC) 被认为是多种同步肺癌中的一个独特疾病实体。很少有研究对这些同步连续病变进行二代测序分析，必须进一步研究 GG/L 结节的遗传改变。方法：我们对 16 名患者的同步非典型腺瘤样增生 (AAH)、原位 ADC 或微创 ADC 的 ADC 进行了靶向测序。使用包含 154 个癌症相关基因的定制面板进行下一代测序。结果：同一患者的多个同步病变表现出不同的突变谱，并且一些具有相同的突变基因。在 5 名携带 EGFR 突变型 ADC 的患者中，他们的同步 GG/L 结节有 EGFR 突变；然而，在 EGFR 野生型 ADC 中没有观察到。AAH、原位ADC、微创ADC和ADC的平均外显子突变数分别为4.2、5.4、4.0和5.4。在每种病变类型中，在 AAH 中观察到各种突变，包括 LDL 受体相关蛋白 1B 基因（LRP1B）、KRAS、EGFR 和 BRAF，其中 EGFR 突变在 ADC 中最常见。总之，在 ADC 中鉴定了 80% 的变异等位基因频率为 20% 或更高的突变，其中包含驱动基因突变。在 ADC 的贴壁区和侵袭区之间发现了肿瘤内遗传谱的异质性，但驱动基因突变是相似的。结论：这项研究表明 ADC 和同步 GG/L 结节是遗传独立的肿瘤。ADC 存在瘤内遗传异质性，但驱动基因突变是均匀分布的。在侵袭性肿瘤中鉴定出具有高变异等位基因频率的驱动基因突变。这些发现支持肺 ADC 和同步 GG/L 结节的分子特征的相关性。