Surrogate Biomarkers of Micrometastatic Gastric Cancer

描述(由申请人提供)： 这项研究的长期目标是开发用于早期发现胃癌微转移的替代分子标志物。胃腺癌是世界上第二大癌症相关死亡原因。尽管美国的患病率为每10万人5-7例，每年新增病例2万例，但胃癌仍占美国所有癌症死亡人数的3%。胃肿瘤主要是(95%)腺癌，早期诊断很少。在诊断时，25%的患者疾病局限于胃，50%的患者有局部区域淋巴结转移和胃外扩散，25%的患者有远处转移。那些表现为局限于胃的癌症患者是根治性胃切除的候选对象。不幸的是，这些患者中约有70%在手术后5年内死于疾病复发。因此，胃微转移的早期检测是临床上的一大挑战。支持这项研究的假设是，在淋巴结中异位胃肿瘤细胞中表达的胃上皮细胞特异性基因是早期发现转移性胃癌的分子标志物。我们的初步数据表明，定量实时RT-PCR很容易检测到人胃活检组织和人胃腺癌细胞中几种mRNA转录本的表达。基于这些和相关的检测肺癌相关mRNAs在纵隔淋巴结中表达的RT-PCR数据，我们提出了两个特定的目标：1)寻找一组用于定量检测胃癌患者恶性淋巴结中可能过度表达的基因的RT-PCR引物对；2)通过筛选胃癌患者的淋巴抽吸物，建立解释标记基因RT-PCR数据的标准。我们预计，这项拟议的研究将为解释通过内窥镜超声-细针抽吸获得的淋巴结细胞的RT-PCR数据建立标准，并将作为在更广泛的患者队列中对定量实时RT-PCR及其与临床结果的相关性进行前瞻性评估的基础。成功开发和验证了基于淋巴结RT-PCR的胃癌微转移检测方法，可能会对临床产生重大影响。

DESCRIPTION (provided by applicant): The long term goal of this study is development of surrogate molecular markers for early detection of micrometastatic stomach cancer. Gastric adenocarcinoma is the second leading cause of cancer-related death in the world. With a U.S. prevalence rate of 5-7 cases per 100,000 population and 20,000 new cases per year, gastric cancer nonetheless accounts for 3% of all U.S. cancer deaths. Gastric neoplasms are predominantly (95%) adenocarcinomas which are rarely diagnosed in their early stages. At diagnosis, 25% of patients have disease confined to the stomach, 50% show locoregional lymph node metastases and extragastric spread, and 25% have distant metastases. Those patients presenting with cancer confined to the stomach are candidates for curative gastric resection. Unfortunately, about 70% of these patients die from disease relapse within 5 years of surgery. Early detection of gastric micrometastases is thus a major clinical challenge. The hypothesis driving the proposed study is that gastric epithelial cell-specific genes expressed in ectopic gastric tumor cells in lymph nodes are molecular markers for early detection of metastatic gastric cancers. Our preliminary data indicate that quantitative real-time RT-PCR readily detects expression of several mRNA transcripts in human gastric biopsies and in human gastric adenocarcinoma cells. Based on these and related RT-PCR data measuring expression of lung cancer-associated mRNAs in mediastinal lymph nodes, we propose two specific aims: 1) To identify a panel of RT-PCR primer pairs for quantitative detection of genes that may be over-expressed in malignant lymph nodes of gastric cancer patients, and 2) To establish criteria for interpretation of marker gene RT-PCR data by screening lymph node aspirates from gastric cancer patients. We anticipate that the proposed study will establish criteria for interpretation of RT-PCR data from lymph node cells acquired by endoscopic ultrasonographic-fine needle aspiration, and will serve as the basis for prospective evaluation of quantitative real-time RT-PCR and its correlation with clinical outcome in a more comprehensive cohort of patients. The successful development and validation of a lymph node RT-PCR-based assay for micrometastatic stomach cancer is likely to have a significant clinical impact.