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，化疗的获益并未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灵敏、可重复且具有成本效益的检测技术（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。我们的团队最近还确定了与转移潜能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具有重要经验，并且具有大量来自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局数据。因此，我们建议：具体目标1：确定一个基因表达特征，可以预测哪些II期结肠癌患者复发并死于转移性疾病。我们将使用新型Illumina DASL寡核苷酸珠阵列（DASL-Colon Recurrent Cancer; DASL-CRC）分析来自120名具有和不具有转移性复发的II期结肠癌患者的肿瘤中的转移基因。 具体目的2：验证DASL-CRC II期结肠癌转移特征。我们将测试以下假设：目标1中生成的DASL-CRC签名可以在第二个非重叠的120个肿瘤组中正确识别死于转移性复发的II期结肠癌患者。总之，该项目将使用最先进的技术来发现和验证FFPE基因表达谱，该基因表达谱可准确预测最有可能死于复发性疾病的II期患者子集，因此最有可能从辅助化疗中获益。 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。该提案旨在确定转移的分子特征，以帮助确定那些将从化疗中获益最多的患者。

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.