Driver Mutations in Normal Airway Epithelium Elucidate Spatiotemporal Resolution of Lung Cancer
Driver Mutations in Normal Airway Epithelium Elucidate Spatiotemporal Resolution of Lung Cancer
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DOI：
10.1164/rccm.201806-1178oc
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发表时间：
2019-09-15
影响因子：
24.7
通讯作者：
Scheet, Paul
中科院分区：
文献类型：
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作者：
Kadara, Humam;Sivakumar, Smruthy;Scheet, Paul
理由：未受累的正常气道上皮已被证明表现出附近非小细胞肺癌 (NSCLC) 的特定突变特征。然而，其在早期NSCLC患者中的体细胞突变状况尚不清楚。目的：全面调查早期NSCLC患者正常气道上皮的体细胞突变结构。方法：多区域正常气道，包括肿瘤邻近的小气道、肿瘤远处的大气道、鼻上皮和未受累的正常肺（统称为气道野）、匹配的NSCLC和来自血细胞（n = 498）通过深度靶向 DNA 测序对 48 名患者进行了体细胞单核苷酸变异的询问，并通过全基因组基因型阵列分析对 48 名患者进行了染色体等位基因不平衡事件的询问。通过系统发育分析评估气道场与 NSCLC 之间的时空关系。测量和主要结果：在 25 例 (52%) 病例中观察到基因组气道场癌变。大多数患者 (n = 36) 的气道野上皮总共表现出 269 种体细胞突变，其中包括与 NSCLC 共有的关键驱动因素。这些获得性变异的等位基因频率在 NSCLC 中总体较高。单核苷酸变异和等位基因失衡事件的综合分析揭示了气道区域中具有共同“两次打击”改变的驱动基因（例如，TP53、KRAS、KEAP1、STK11和CDKN2A）以及非小细胞肺癌中单次打击进展到两次的驱动基因（例如，PIK3CA和NOTCH1）。结论：邻近肿瘤和远离肿瘤的正常外观气道上皮表现出体细胞驱动改变，在非小细胞肺癌中经历选择驱动的克隆扩张。这些事件为非小细胞肺癌的发展提供了时空见解，从而为早期治疗提供了潜在的目标。
Rationale: Uninvolved normal-appearing airway epithelium has been shown to exhibit specific mutations characteristic of nearby non-small cell lung cancers (NSCLCs). Yet, its somatic mutational landscape in patients with early-stage NSCLC is unknown.Objectives: To comprehensively survey the somatic mutational architecture of the normal airway epithelium in patients with early-stage NSCLC.Methods: Multiregion normal airways, comprising tumor-adjacent small airways, tumor-distant large airways, nasal epithelium and uninvolved normal lung (collectively airway field), matched NSCLCs, and blood cells (n = 498) from 48 patients were interrogated for somatic single-nucleotide variants by deep-targeted DNA sequencing and for chromosomal allelic imbalance events by genome-wide genotype array profiling. Spatiotemporal relationships between the airway field and NSCLCs were assessed by phylogenetic analysis.Measurements and Main Results: Genomic airway field carcinogenesis was observed in 25 cases (52%). The airway field epithelium exhibited a total of 269 somatic mutations in most patients (n = 36) including key drivers that were shared with the NSCLCs. Allele frequencies of these acquired variants were overall higher in NSCLCs. Integrative analysis of single-nucleotide variants and allelic imbalance events revealed driver genes with shared "two-hit" alterations in the airway field (e.g., TP53, KRAS, KEAP1, STK11, and CDKN2A) and those with single hits progressing to two in the NSCLCs (e.g., PIK3CA and NOTCH1).Conclusions: Tumor-adjacent and tumor-distant normal-appearing airway epithelia exhibit somatic driver alterations that undergo selection-driven clonal expansion in NSCLC. These events offer spatiotemporal insights into the development of NSCLC and, thus, potential targets for early treatment.