Molecular strategies to define carcinoids and rationalize surgical intervention

定义类癌并使手术干预合理化的分子策略

• 批准号: 7096260
• 负责人: IRVIN M MODLIN
• 金额: $ 29.29万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-27 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7096260
• 关键词: clinical research; gene expression; genes; liver; lymph nodes; metastasis; neoplasm /cancer; tissues

DESCRIPTION (provided by applicant): The commonest gastrointestinal (Gl) carcinoids occur in the small intestine and appendix. Both are derived from the enterochromaffin (EC) cell, but their malignancy and propensity to metastasize vary widely. Small intestinal carcinoids (SICs) are aggressive and exhibit hepatic and lymph node (LN) metastasis; appendiceal carcinoids (APCs) are slow-growing and rarely metastasize. Gastric carcinoids (GCs) [enterochromaffin-like (ECL) cells], are slow-growing and rarely metastasize unless gastrin-independent. No biological explanation for the variable malignancy of Gl carcinoids exists. We hypothesize that a gene expression-based definition of these tumors will: 1) allow prediction of malignancy and metastasis, and 2) provide accurate staging and facilitate rational therapy. Utilizing: i) GeneChip analysis, ii) quantitative real-time PCR (Q RT-PCR), and iii) carcinoid tissue microarray (TMA) immunostaining/quantitation, we evaluated gene and protein expression in Gl carcinoids. In SICs and their metastases, the neuroendocrine marker chromogranin A (CgA); NAP1L1 (mitosis regulator); MAGE-D2 (liver metastatic predictor), and MTA1 (metastasis, migration), are over- expressed. In malignant APCs and GCs, CgA, MAGE-D2, MTA1, and NAP1L1 are all significantly over- expressed. In 30% of histologically-negative lymph nodes, molecular analysis detected CgA transcript and protein, making sensitive molecular staging of carcinoid tumors possible. This proposal seeks, using Q RT- PCR of frozen and paraffin specimens and carcinoid TMA analysis, to define the malignant potential of Gl carcinoids. The aims are: 1) Confirm the specificity of the neuroendocrine cell marker gene, CgA, in identifying Gl carcinoids, 2) Determine whether increased levels of the mitotic and metastasis-associated genes, NAP1L1, MAGE-D2 and MTA1, characterize malignant Gl carcinoids, 3) Determine whether benign and malignant appendiceal carcinoids show predictive differential gene expression, and 4) Identify occult metastasis in histologically normal lymph node or liver biopsies using Q RT-PCR. We propose that delineation and quantification of gene expression will: 1) define malignancy of an individual carcinoid and 2) identify occult metastasis. This will provide novel biological information and provide molecular data to identify occult metastasis predict spread and facilitate preemptive appropriate therapy.

描述（由申请人提供）：最常见的胃肠道（GI）类癌发生在小肠和阑尾。两者都来源于肠嗜铬（EC）细胞，但它们的恶性程度和转移倾向差异很大。小肠类癌（SIC）具有侵袭性，并表现出肝和淋巴结（LN）转移;阑尾类癌（APC）生长缓慢，很少转移。胃类癌（GC）[肠嗜铬样（ECL）细胞]生长缓慢，除非不依赖胃泌素，否则很少转移。没有生物学解释的可变恶性GI类癌存在。我们假设，基于基因表达的肿瘤定义将：1）允许预测恶性和转移，2）提供准确的分期和促进合理的治疗。利用：i）基因芯片分析，ii）定量实时PCR（QRT-PCR），和iii）类癌组织微阵列（TMA）免疫染色/定量，我们评估了GI类癌中的基因和蛋白质表达。在SIC及其转移中，神经内分泌标志物嗜铬粒蛋白A（CgA）、NAP 1 L1（有丝分裂调节剂）、MAGE-D2（肝转移预测因子）和MTA 1（转移、迁移）过表达。在恶性APC和GC中，CgA、MAGE-D2、MTA 1和NAP 1 L1都显著过表达。在30%的组织学阴性淋巴结中，分子分析检测到CgA转录物和蛋白，使类癌的敏感分子分期成为可能。该建议旨在使用冷冻和石蜡标本的QRT-PCR和类癌TMA分析来确定GI类癌的恶性潜能。其目标是：1）确认神经内分泌细胞标记基因CgA在鉴定GI类癌中的特异性，2）确定有丝分裂和转移相关基因NAP 1 L1、MAGE-D2和MTA 1的水平增加是否表征恶性GI类癌，3）确定良性和恶性阑尾类癌是否显示预测性差异基因表达，和4）使用Q RT-PCR鉴定组织学正常的淋巴结或肝活检中的隐匿性转移。我们建议，基因表达的描绘和定量将：1）确定一个单独的类癌的恶性程度和2）确定隐匿性转移。这将提供新的生物学信息和分子数据，以确定隐匿性转移，预测扩散和促进先发制人的适当治疗。