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，化疗的好处并不明显超过不良事件的相关发病率。因此，欧洲和美洲的大多数II期疾病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敏感、可重复性和成本效益高的分析技术(DASL)，可以从常规收集的福尔马林固定石蜡包埋(FFPE)组织样本中生成高质量的RNA表达谱。我们的团队最近还发现了与(前列腺癌)转移潜能相关的基因表达特征，在新型基因阵列的成功设计和应用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样本，这些患者具有良好的转移复发、无进展生存期和其他临床结果数据。因此，我们建议：特异性目的1：确定一个基因表达特征，可以预测哪些II期结肠癌患者复发和死于转移性疾病。我们将使用一种新的Illumina DASL寡核苷酸珠阵列(DASL-COLON REPLATE HOC；DASL-CRC)来分析120名有转移复发和无转移复发的II期结肠癌患者的肿瘤转移基因。 具体目的2：验证DASL-CRC II期结肠癌转移标志物。我们将测试这样一个假设，即在AIM 1中生成的DASL-CRC签名可以在第二组非重叠的120个肿瘤中正确地识别死于转移复发的II期结肠癌患者。总而言之，该项目将使用最先进的技术来发现和验证FFPE基因表达谱，该谱准确预测最有可能死于复发疾病的II期患者的子集，因此他们最有可能从辅助化疗中受益。 公共卫生相关性：对于II期结肠癌患者，化疗的益处并不明显超过不良事件的相关发病率。这项建议旨在确定转移的分子特征，以帮助确定哪些患者将从化疗中受益最大。

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.