DASL-CRC: A Novel Approach to Identify Molecular Markers of Metastatic Recurrence

描述（由申请人提供）：对于II期结肠癌患者，化疗的益处并不明显超过相关不良事件的发病率。因此，在欧洲和美洲，大多数II期患者在手术后不接受辅助化疗。不幸的是，25-30%的II期结肠癌患者在6年内复发并死于转移性疾病。我们的团队最近开发了一种灵敏、可重复且经济有效的检测技术（DASL），可以从常规收集的福尔马林固定石蜡包埋（FFPE）组织标本中生成高质量的RNA表达谱。我们的团队最近还发现了与转移潜力相关的基因表达特征（在前列腺癌中），在成功设计和应用新型基因阵列方面拥有丰富的经验，并拥有大量来自II期结肠癌患者的FFPE标本，这些患者具有良好的转移复发特征，无进展生存期和其他临床结果数据。因此，我们提出：特异性目标1：确定一种基因表达特征，可以预测哪些II期结肠癌患者复发并死于转移性疾病。我们将使用一种新型Illumina DASL寡核苷酸头阵列（DASL- colon Recurrent cancer; DASL- crc）分析120例伴有或未伴有转移性复发的II期结肠癌患者的肿瘤转移基因。

DESCRIPTION (provided by applicant): For Stage II colon cancer patients, the benefits of chemotherapy do not clearly outweigh the associated morbidity from adverse events. The majority of patients with stage II disease in Europe and the Americas therefore do not receive adjuvant chemotherapy after surgery. Unfortunately, 25-30% of stage II colon cancer patients relapse and die from metastatic disease within 6 years. Our team has recently developed a sensitive, reproducible and cost effective assay technology (DASL) that can generate high quality RNA expression profiles from routinely collected formalin fixed paraffin embedded (FFPE) tissue specimens. Our team has also recently identified gene expression signatures associated with metastatic potential (in prostate cancer), has significant experience in the successful design and application of novel gene arrays, and has substantial numbers of FFPE specimens from Stage II colon cancer patients with well characterized metastatic recurrence, progression free survival and other clinical outcome data. We therefore propose: SPECIFIC AIM 1: To identify a gene expression signature that can predict which stage II colon cancer patients relapse and die from metastatic disease. We will profile metastasis genes in tumors from 120 stage II colon cancer patients with and without metastatic recurrence using a novel Illumina DASL oligonucleotide bead array (DASL- Colon Recurrent Cancer; DASL-CRC). SPECIFIC AIM 2: To validate the DASL-CRC stage II colon cancer metastasis signature. We will test the hypothesis that the DASL-CRC signature generated in Aim 1 can correctly identify in a second, non-overlapping set of 120 tumors the stage II colon cancer patients who die from metastatic relapse. In summary, this project will use state of the art technology to discover and validate an FFPE gene expression profile that accurately predicts the subset of Stage II patients who are most likely to die from recurrent disease, and who therefore are most likely to benefit from adjuvant chemotherapy. PUBLIC HEALTH RELEVANCE: For Stage II colon cancer patients, the benefits of chemotherapy do not clearly outweigh the associated morbidity from adverse events. This proposal seeks to identify a molecular signature of metastasis to help identify those patients who will benefit most from chemotherapy.