Weber Frank, Xu Yaomin, Zhang Li, Patocs Attila, Shen Lei, Platzer Petra, Eng Charis
Genomic Medicine Institute and Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA.
JAMA. 2007 Jan 10;297(2):187-95. doi: 10.1001/jama.297.2.187.
Carcinogens associated with head and neck squamous cell carcinoma (SCC) genesis should inflict genomic alterations not only on the epithelium but also the mesenchyme of the aerodigestive tract. Therefore, the apparently nonmalignant stroma surrounding the tumor epithelium can acquire genomic alterations and contribute to cancer initiation and progression.
To determine compartment-specific loci of loss of heterozygosity or allelic imbalance (LOH/AI) and to identify which genomic alterations restricted to the stroma cell population contribute to aggressiveness of head and neck SCC disease.
DESIGN, SETTING, AND PATIENTS: Tumor epithelium and surrounding stroma were isolated from 122 US patients with oral cavity and oropharyngeal or hypopharyngeal SCC and subjected to whole-genome LOH/AI analysis using 366 microsatellite markers. Samples, collected between 2001 and 2004, were pulled and transferred in batches of 10 to 30 between 2002 and 2005. Laser capture microdissection DNA extraction and technical genotyping occurred on a rolling model between 2002 and November 2005.
Compartment-specific frequency and distribution of LOH/AI were determined, and hot spots of genomic alterations identified. Compartment-specific LOH/AI events were correlated with presenting clinicopathologic characteristics.
Tumor-associated stroma of head and neck SCC from smokers were found to have a high degree of genomic alterations. A correlation between tumor aggressiveness could be found for a specific set of 5 loci. Three stroma-specific loci (D4S2417, D3S360, and D19555) were associated with tumor size (pT) and regional nodal metastases (pN). Furthermore, 2 epithelial-specific LOH/AI hot spots were positively correlated with pN status and clinical stage.
Stroma-specific genetic alterations are associated with smoking-related head and neck SCC genesis. These findings suggest novel prognostic or diagnostic biomarkers and identify potential new molecular targets for therapeutic and preventive intervention.
与头颈部鳞状细胞癌（SCC）发生相关的致癌物不仅应在上皮细胞中引起基因组改变，还应在消化道的间充质中引起改变。因此，肿瘤上皮周围明显非恶性的基质可获得基因组改变，并促进癌症的发生和发展。
确定杂合性缺失或等位基因失衡（LOH/AI）的特定区域位点，并确定哪些仅限于基质细胞群体的基因组改变会导致头颈部SCC疾病的侵袭性。
设计、地点和患者：从122名美国口腔、口咽或下咽SCC患者中分离出肿瘤上皮和周围基质，并使用366个微卫星标记进行全基因组LOH/AI分析。2001年至2004年期间收集的样本在2002年至2005年期间以10至30个样本为一批进行提取和转移。2002年至2005年11月期间，采用滚动模式进行激光捕获显微切割DNA提取和技术基因分型。
确定LOH/AI的特定区域频率和分布，并识别基因组改变的热点。特定区域的LOH/AI事件与呈现的临床病理特征相关。
发现吸烟者头颈部SCC的肿瘤相关基质具有高度的基因组改变。对于一组特定的5个位点，可发现肿瘤侵袭性之间存在相关性。三个基质特异性位点（D4S2417、D3S360和D19S555）与肿瘤大小（pT）和区域淋巴结转移（pN）相关。此外，2个上皮特异性LOH/AI热点与pN状态和临床分期呈正相关。
基质特异性基因改变与吸烟相关的头颈部SCC发生有关。这些发现提示了新的预后或诊断生物标志物，并确定了治疗和预防干预的潜在新分子靶点。
