Genomic Landscape Established by Allelic Imbalance in the Cancerization Field of a Normal Appearing Airway
Genomic Landscape Established by Allelic Imbalance in the Cancerization Field of a Normal Appearing Airway
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DOI：
10.1158/0008-5472.can-15-3064
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发表时间：
2016-07-01
期刊：
影响因子：
11.2
通讯作者：
Kadara, Humam
中科院分区：
文献类型：
--
作者：
Jakubek, Yasminka;Lang, Wenhua;Kadara, Humam
邻近肺肿瘤并从肺肿瘤延伸的视觉正常细胞可能携带肿瘤本身的分子改变特征，这种效应称为气道癌变场。该气道野被假定为肺癌发病机制中早期事件的模型。然而，肺癌患者气道上皮细胞体细胞获得性分子改变的基因组景观仍然未知。为了开始填补这一空白，我们试图全面表征在最常见类型的肺肿瘤，非小细胞肺癌（NSCLC）的气道领域中诱导等位基因不平衡（AI）的染色体改变的基因组结构。为此，我们对45例早期NSCLC患者的多个空间分布的正常气道、多区域肿瘤标本和未受累的正常组织或血液进行了全基因组调查。我们检测了22例患者的气道上皮细胞的改变，鳞状组织学NSCLC的频率增加。我们的数据还表明，在更接近NSCLC的样本中，AI存在空间梯度。9号染色体显示出最高水平的AI，并包括复发的独立事件。此外，在已知的NSCLC驱动因素中，气道领域AI包括致癌增益和肿瘤抑制因子丢失。我们的研究结果表明，全基因组AI在气道癌变领域很常见，为NSCLC发病机制中的早期事件提供了见解，这些事件可能包括早期治疗和化学预防的靶点。(C)2016年AACR。
Visually normal cells adjacent to, and extending from, tumors of the lung may carry molecular alterations characteristics of the tumor itself, an effect referred to as airway field of cancerization. This airway field has been postulated as a model for early events in lung cancer pathogenesis. Yet the genomic landscape of somatically acquired molecular alterations in airway epithelia of lung cancer patients has remained unknown. To begin to fill this void, we sought to comprehensively characterize the genomic architecture of chromosomal alterations inducing allelic imbalance (AI) in the airway field of the most common type of lung tumors, non-small cell lung cancer (NSCLC). To do so, we conducted a genome-wide survey of multiple spatially distributed normal-appearing airways, multiregion tumor specimens, and uninvolved normal tissues or blood from 45 patients with early-stage NSCLC. We detected alterations in airway epithelia from 22 patients, with an increased frequency in NSCLCs of squamous histology. Our data also indicated a spatial gradient of AI in samples at closer proximity to the NSCLC. Chromosome 9 displayed the highest levels of AI and comprised recurrent independent events. Furthermore, the airway field AI included oncogenic gains and tumor suppressor losses in known NSCLC drivers. Our results demonstrate that genome-wide AI is common in the airway field of cancerization, providing insights into early events in the pathogenesis of NSCLC that may comprise targets for early treatment and chemoprevention. (C) 2016 AACR.