Analysis of genetic alterations in esophageal squamous cell carcinoma and epithelial neoplasm of borderline malignancy-for application to genetic diagnosis

食管鳞状细胞癌（Esophageal squamous cell carcinoma，ESC）是一个多阶段的进展过程，包括正常鳞状上皮转化为基底细胞增生（basal cell hyperplasia，BCH）和被认为是ESC前病变的不典型增生（dysplasia），然后转化为浸润性鳞状细胞癌（invasive squamous cell carcinoma，SCC）。据推测，多种遗传改变的多步骤积累过程与ESC的癌变相关。我们研究了5例手术切除的浅表多灶性食管SCC。应用显微解剖区域提取的DNA，分析了SCC、BCH、异型增生和正常食管上皮中p53基因突变、杂合性丢失（洛）和微卫星不稳定性（MSI）。p53基因接触突变和洛缺失不仅见于鳞状细胞癌，也见于不典型增生、BCH、甚至组织学正常的上皮。提示p53基因的异常是ESCs多阶段癌变的早期关键事件之一。高频 关于我们 同时检测癌旁组织和SCC中DNA错配修复基因的MSI和洛。这些结果支持错配修复系统的缺陷可能导致浅表ESCs的多灶性癌变。此外，为了评估粘附分子在ESCs的进展和转移中的作用，我们研究了71例原发性肿瘤及其相应的淋巴结转移瘤中各种粘附分子（E-cadherin、β-catenin、integrin β1、CD 44和CD 44 v6）的表达与临床病理因素之间的关系。关于临床病理特征，发现原发肿瘤中粘附分子表达的降低与浸润深度、淋巴结转移、淋巴和血管渗透显著相关。E-cadherin、β-catenin和CD 44 v6在转移淋巴结中表达的降低与转移淋巴结数目的增加显著相关。对原发肿瘤和转移淋巴结中各种粘附分子的综合分析表明，粘附分子的改变是影响ESCs侵袭性、转移潜能和预后的重要因素。少

Esophageal squamous cell carcinoma (ESC) is a multistage progressive process that involves the conversion of normal squamous epithelium to that with basal cell hyperplasia (BCH), dysplasia that are thought to be precursor lesions of ESC, and then to invasive squamous cell carcinoma (S CC). It is speculated that the multistep process of accumulation of various genetic alterations correlates with the carcinogenesis of ESC. We studied five surgically resected superficial multifocal esophageal SCCs. p53 gene mutation, loss of heterozygosity (LOH), and microsatellite instability (MSI) were analyzed in SCC, BCH, dysplasia and normal esophageal epithelium, using DNA extracted from microdissected areas. Contact mutation and LOH of p53 gene were identified not only in SCC but also in dysplasia, BCH, and even in histologically normal epithelium. These findings indicated that aberrations of p53 gene are one of the key events in early phase of multistage carcinogenesis of ESCs. The high frequency … More of MSI and LOH of DNA mismatch repair gene were detected simultaneously in non-cancerous lesions and SCCs. These results supported that the deficiency of the mismatch repair system probably induces multifocal carcinogenesis of superficial ESCs. Furthermore, to evaluate the role of adhesion molecules in the progression and metastasis of ESCs, the correlation between the clinicopathological factors and the expression of various adhesion molecules (E-cadherin, β-catenin, integrin β1, CD44 and CD44v6) was studied in 71 primary tumors and their corresponding nodal metastases. Regarding the clinicopathological features, a reduced expression of adhesion molecules in primary tumors was found to be significantly associated with depth of invasion, lymph node metastasis, lymph and blood vessel permeations. The reduced expression of E-cadherin, β-catenin and CD44v6 in the metastatic lymph nodes was significantly correlated with the increased number of metastatic lymph nodes. The comprehensive analysis of various adhesion molecules not only in primary tumors but also in metastatic lymph nodes demonstrated that the alterations of adhesion molecules are important factors significantly influencing invasiveness, metastatic potential, and prognosis in ESCs. Less