GENETIC MARKERS FOR THERAPY OF COLON CANCER

描述：(申请人的描述)癌症的敏感性和抗药性 细胞对化疗的影响很复杂。分子遗传学的进展 明确的凋亡和细胞周期控制通路受以下因素影响 化疗药物。这些途径中的基因提供了新的预后 治疗反应的标记物。 这项研究将检验以下假设：基因的改变 负责控制细胞凋亡和细胞周期途径的是标记物 结肠癌患者对辅助化疗的耐受性和 转移性结肠癌的化疗。 为了解决这一假设，我们提出了以下具体目标：评估 人外周血中KILTER/DR5死亡受体基因区的等位基因缺失状态 8号染色体短臂(8p21)和P53抑制基因的p73同源基因 1号染色体短臂(1p36)上的基因区域，以及该基因的表达 结肠腺癌中细胞周期蛋白依赖性激酶2抑制物p27/Kip1的研究 我们将评估的癌症来自于闭合的ECOG辅助化疗 协议E2284和E2288作为现有相关协议的扩展 E3293和El294与晚期结肠腺癌转移 疾病化疗方案E2290。我们还建议将相关扩展到 免疫组织化学和17P法检测E3293和E1294对p53基因表达的影响 等位基因缺失，染色体18q、p21/WAF1上DCC基因区缺失 表达和DNA复制错误(RER，微卫星不稳定性) E2290。基因改变将在生存分析和 术后反应分析以确定其作为预后标志物的有效性 化疗。

DESCRIPTION: (Applicant's Description) 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.