MOLECULAR MARKERS IN ESOPHAGEAL ADENOCARCINOMA

已有多个肿瘤抑制基因座的染色体等位基因丢失和基因改变在食管腺癌中的报道。我们在以前的相关研究中发现，18q染色体缺失是结肠癌术后辅助化疗患者的不良预测指标。化疗药物诱导细胞凋亡，因此，从理论上讲，细胞凋亡、复制和细胞周期调节的改变可能会影响治疗反应。这项建议的目标是在食道远端和食管胃交界处(EGJ)的腺癌患者中解决我们在结肠癌中对染色体18q丢失的发现，并开发更多新的导致基因改变的新线索，并对术后辅助治疗的预后产生影响。我们建议评估两个针对基因改变的假说作为食管腺癌化疗反应的预测标记物：1.18q等位基因丢失将导致术后辅助治疗后较差的存活率。2.完整的细胞凋亡、DNA合成和细胞周期控制通路将导致术后辅助化疗后更好的生存。为了解决第一个假设，具体目标1是在东方合作肿瘤学小组(ECOG)的临床试验E8296中表征食管腺癌和EGJ腺癌的18q等位基因丢失的特征，并将结果与生存相关。我们将通过聚合酶链式反应从肿瘤常规组织切片中扩增DNA，用一组微卫星标记评估18q等位基因丢失。生存分析将由经社理事会统计中心进行。对于第二个假设，特定的目标2是表征细胞凋亡、DNA合成和细胞周期控制途径，并将结果与生存相关。我们将使用一组抗体(bcl2、bclxL、bax、p53、p21WAF1、p27Kip1、CyclinD1、Ki-67)和等位基因丢失(染色体17p)来描述这些途径，并将结果与生存相关。本研究将为18q等位基因缺失作为食管腺癌术后辅助化疗预测标志物的应用提供重要信息。这项研究还将指导未来作为合作小组背景下的标记物的凋亡、DNA合成和细胞周期控制通路的研究。

Multiple chromosomal allelic losses in tumor suppressor gene loci and genetic alterations have been reported in esophageal adenocarcinomas. We have shown in previous correlative studies E3293 and E1294 that loss of chromosome 18q is an adverse predictive marker for patients with colon cancer treated with postoperative adjuvant chemotherapy. Chemotherapeutic agents induce apoptosis, and, therefore, in theory, alterations in apoptosis, replication and cell cycle regulation may affect therapeutic response. The goals of this proposal are to address in patients with adenocarcinoma in the distal esophagus and esophagogastric junction (EGJ) our findings on chromosome 18q loss in colon cancer and to develop additional new leads to the genetic alterations with prognostic implications for post-operative adjuvant therapy. We propose to evaluate two hypotheses addressed at genetic alterations as predictive markers for chemotherapeutic response in esophageal adenocarcinomas: 1. Allelic loss of chromosome 18q will lead to worse survival after post- operative adjuvant therapy. 2. Intact apoptotic, DNA synthetic, and cell cycle control pathways will result in better survival after post-operative adjuvant chemotherapy. To address the first hypotheses, Specific Aim number 1 is to characterize allelic loss of 18q in esophageal and EGJ adenocarcinomas in clinical trial E8296 of the Eastern Cooperative Oncology Group (ECOG) and correlate the results with survival. We will assess 18q allelic loss with a panel of microsatellite markers by polymerase chain reaction amplication of DNA from routine histological sections of tumors. Survival analyses will be carried out by the ECOG Statistical Center. For the second hypothesis, Specific Aim number 2 is to characterize apoptotic, DNA synthetic and cell cycle control pathways and correlate the results with survival. We will use immunohistochemistry with a panel of antibodies (bcl2, bclxL, bax, p53, p21WAF1, p27Kip1, cyclinD1, Ki-67) and allelic loss (chromosome 17p) to characterize the pathways and correlate the findings with survival. This study will provide important information about the potential utility of chromosome 18q allelic loss as a predictive marker in patients with esophageal adenocarcinoma treated with postoperative adjuvant chemotherapy. The study will also direct future studies of apoptotic, DNA synthetic, and cell cycle control pathways as markers in the cooperative group setting.