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.
