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

食管鳞状细胞癌和交界性恶性肿瘤上皮性肿瘤的基因改变分析及其在基因诊断中的应用

• 批准号: 13670196
• 负责人: HARAOKA Seiji
• 金额: $ 1.92万
• 依托单位: Fukuoka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670196/
• 关键词: esophagus; squamous cell carcinoma; pathology; genetic alteration; loss of heterozygoisity (LOH); microsatellite instability; adhesion molecule; lymph node metastasis; cDNAマイクロアレイ; 予後; 多発表在癌; p53遺伝子異常; microsatellite instability (MSI); replic

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

食管鳞癌是一个多阶段的进展性过程，由正常鳞状上皮向基底细胞增生、不典型增生转化，进而发展为侵袭性鳞状细胞癌(S，CC)。推测多种基因改变的多步累积过程与ESC的发生有关。我们研究了五例手术切除的浅表多灶性食管鳞癌。采用显微切割组织提取DNA，检测鳞癌、BCH、异型增生和正常食道上皮组织中P53基因突变、杂合性缺失(LOH)和微卫星不稳定性(MSI)。P53基因的接触性突变和LOH不仅在鳞癌中存在，而且在异型增生、BCH中也存在，甚至在组织学正常的上皮中也存在。提示P53基因异常是ESCs多阶段癌变早期的关键事件之一。高频…DNA错配修复基因的MSI和LOH在非癌病变和鳞癌中同时检测到较多。这些结果支持错配修复系统的缺失可能导致浅表ESCs的多灶性癌变。此外，为探讨黏附分子在ESCs进展和转移中的作用，我们研究了71例原发肿瘤及其相应的淋巴结转移灶中各种黏附分子(E-钙粘素、β-连环蛋白、整合素β1、CD44和CD44v6)的表达与临床病理因素的关系。在临床病理特征方面，黏附分子在原发肿瘤中的表达降低与肿瘤的侵袭深度、淋巴结转移、淋巴和血管渗透显著相关。E-钙粘蛋白、β-连环素和CD44v6在转移淋巴结中的表达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黏附分子的综合分析表明，黏附分子的变化是影响ESCs侵袭力、转移潜能和预后的重要因素。较少

项目成果

Nariyoshi Takayama, Sumitaka Arima, Seiji Haraoka, et al.: "Relationship between the expression of adhesion molecules in primary esophageal squamous cell carcinoma and metastatic lymph nodes."Anticancer research. 23. 4435-4442 (2003)

Nariyoshi Takayama、Sumitaka Arima、Seiji Haraoka 等：“原发性食管鳞状细胞癌与转移性淋巴结中粘附分子表达的关系”。抗癌研究。

Takehiro Fujiki, Seiji Haraoka, et al.: "p53 gene mutation and genetic instability in superficial multifocal esophageal squamous cell carcinoma"International Journal of Oncology. 20. 669-679 (2002)

Takehiro Fujiki、Seiji Haraoka 等人：“浅表多灶性食管鳞状细胞癌中的 p53 基因突变和遗传不稳定性”国际肿瘤学杂志。

Fujiki T, Haraoka S, Yoshioka S, Ohshima K, Iwashita A, Kikuchi M: "p53 gene mutation and genetic instability in superficial multifocal esophageal squamous cell carcinoma."Int J Oncol. 20. 669-679 (2002)

Fujiki T、Haraoka S、Yoshioka S、Ohshima K、Iwashita A、Kikuchi M：“浅表多灶性食管鳞状细胞癌中的 p53 基因突变和遗传不稳定性。”Int J Oncol。

Nariyoshi Takayama, Sumitaka Arima, Seiji Haraoka, et al.: "Relationship between the enpression of adhesion molecules in primary esophageal squamous cell carcinoma and metastatic lymph nodes."Anticancer research. 23. 4435-4442 (2003)

Nariyoshi Takayama、Sumitaka Arima、Seiji Haraoka 等：“原发性食管鳞状细胞癌中粘附分子的压迫与转移性淋巴结之间的关系。”抗癌研究。

Takayama N, Arima S, Haraoka S, Kotho T, Futami K, Iwashita A: "Relationship between the expression of adhesion molecules in primary esophageal squamous cell carcinoma and metastatic lymph nodes."Anticancer Res. 23. 4435-4442 (2003)

Takayama N、Arima S、Haraoka S、Kotho T、Futami K、Iwashita A：“原发性食管鳞状细胞癌和转移性淋巴结中粘附分子表达的关系。”抗癌研究。