Centre for Respiratory Research, Royal Free and University College Medical School, London, United Kingdom.
Am J Respir Crit Care Med. 2010 Jul 1;182(1):83-91. doi: 10.1164/rccm.201001-0005OC. Epub 2010 Mar 18.
Amplification of distal 3q is the most common genomic aberration in squamous lung cancer (SQC). SQC develops in a multistage progression from normal bronchial epithelium through dysplasia to invasive disease. Identifying the key driver events in the early pathogenesis of SQC will facilitate the search for predictive molecular biomarkers and the identification of novel molecular targets for chemoprevention and therapeutic strategies. For technical reasons, previous attempts to analyze 3q amplification in preinvasive lesions have focused on small numbers of predetermined candidate loci rather than an unbiased survey of copy-number variation.
To perform a detailed analysis of the 3q amplicon in bronchial dysplasia of different histological grades.
We use molecular copy-number counting (MCC) to analyze the structure of chromosome 3 in 19 preinvasive bronchial biopsy specimens from 15 patients and sequential biopsy specimens from 3 individuals.
We demonstrate that no low-grade lesions, but all high-grade lesions, have 3q amplification. None of seven low-grade lesions progressed clinically, whereas 8 of 10 patients with high-grade disease progressed to cancer. We identify a minimum commonly amplified region on chromosome 3 consisting of 17 genes, including 2 known oncogenes, SOX2 and PIK3CA. We confirm that both genes are amplified in all high-grade dysplastic lesions tested. We further demonstrate, in three individuals, that the clinical progression of high-grade preinvasive disease is associated with incremental amplification of SOX2, suggesting this promotes malignant progression.
These findings demonstrate progressive 3q amplification in the evolution of preinvasive SQC and implicate SOX2 as a key target of this dynamic process.
远端 3q 扩增是鳞状肺癌（SQC）最常见的基因组异常。SQC 是从正常支气管上皮经异型增生到浸润性疾病的多阶段进展而来。鉴定 SQC 早期发病机制中的关键驱动事件将有助于寻找预测性分子生物标志物，并确定化学预防和治疗策略的新分子靶点。由于技术原因，先前在研究早期病变时对 3q 扩增的分析主要集中在少数预定的候选基因座上，而不是对拷贝数变化进行无偏倚的调查。
对不同组织学分级的支气管异型增生中 3q 扩增子进行详细分析。
我们使用分子拷贝数计数（MCC）分析 15 名患者的 19 例支气管活检术前病变标本和 3 名患者的序贯活检标本中 3 号染色体的结构。
我们证明，只有高级别病变而不是所有低级别病变都有 3q 扩增。7 例低级别病变中无 1 例临床进展，而 10 例高级别病变中有 8 例进展为癌症。我们确定了染色体 3 上由 17 个基因组成的最小共同扩增区域，包括 2 个已知的癌基因 SOX2 和 PIK3CA。我们证实，在所有检测到的高级别异型增生病变中，这两个基因均被扩增。我们进一步在 3 名患者中证明，高级别癌前病变的临床进展与 SOX2 的逐渐扩增相关，提示这促进了恶性进展。
这些发现表明，在 SQC 癌前病变的进展过程中存在逐渐的 3q 扩增，并提示 SOX2 是这一动态过程的关键靶基因。
