) Sensitivity and resistance of cancer cells to chemotherapy are complex. Advances in molecular genetics have defined apoptotic and cell-cycle control pathways which are affected by chemotherapeutic agents. Genes in these pathways offer new prognostic markers for therapeutic response. This study will test the following hypothesis: Alterations in genes responsible for control of the apoptotic and cell cycle pathways are markers for resistance to adjuvant chemotherapy in colonic carcinomas and to chemotherapy in metastatic colonic carcinomas. To address this hypothesis, we propose the following specific aim: Evaluate allelic loss status of the KILLER/DR5 death-receptor gene region on the short arm of chromosome 8 (8p21) and the p73 homolog of the p53 suppressor gene region on the short arm of chromosome 1 (1p36), and expression of the cyclin-dependent kinase 2 inhibitor p27/Kip1 in colonic adenocarcinomas. The cancers we will evaluate are from closed ECOG adjuvant chemotherapy protocols E2284 and E2288 as an extension of existing correlative protocols E3293 and El294 and metastatic colonic adenocarcinomas in closed advanced disease chemotherapy protocol E2290. We also propose to extend correlative studies E3293 and E1294 to evaluate p53 by immunohistochemistry and 17p allelic loss, loss of the DCC gene region on chromosome 18q, p21/WAF1 expression, and DNA replication errors (RER, microsatellite instability) in E2290. The genetic alterations will be evaluated in survival analysis and analysis of response to determine their utility as prognostic markers after chemotherapy.
| Alexander, J; Watanabe, T; Wu, T T et al. (2001) Histopathological identification of colon cancer with microsatellite instability. Am J Pathol 158:527-35 |
