Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.
Division of Statistics, Medical Research Collaborating Center, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.
J Thorac Oncol. 2018 Nov;13(11):1776-1783. doi: 10.1016/j.jtho.2018.07.097. Epub 2018 Aug 16.
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.
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.
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.
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.
肺腺癌（ADC）伴同步磨玻璃/贴壁（GG/L）结节在多灶性同步肺癌中被视为一种独特的疾病实体。很少有研究对这些同步序贯病变进行下一代测序分析，因此必须进一步研究 GG/L 结节的遗传改变。
我们对 16 例伴有不典型腺瘤样增生（AAH）、原位 ADC 或微浸润性 ADC 的 ADC 患者的同步不典型腺瘤样增生、原位 ADC 或微浸润性 ADC 进行了靶向测序。下一代测序是通过使用包括 154 个癌症相关基因的定制面板进行的。
同一患者的多个同步病变显示出不同的突变谱，并且一些共享相同的突变基因。在 5 例 EGFR 突变型 ADC 患者中，其同步 GG/L 结节存在 EGFR 突变；然而，在 EGFR 野生型 ADC 中则未观察到。AAH、原位 ADC、微浸润性 ADC 和 ADC 中的外显子突变平均数量分别为 4.2、5.4、4.0 和 5.4。在每种病变类型中，AAH 中观察到包括 LDL 受体相关蛋白 1B 基因（LRP1B）、KRAS、EGFR 和 BRAF 在内的各种突变，而 EGFR 突变在 ADC 中最为常见。所有突变中，等位基因变异频率为 20%或更高的突变中，包含驱动基因突变的比例为 80%，在 ADC 中被鉴定出来。在 ADC 的贴壁和侵袭区域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。
本研究表明，ADC 和同步 GG/L 结节是遗传上独立的肿瘤。ADC 存在肿瘤内遗传异质性，但驱动基因突变均匀分布。在侵袭性肿瘤中发现了高频等位基因突变的驱动基因。这些发现支持对肺 ADC 和同步 GG/L 结节进行分子特征分析的相关性。
