Development of a Urine Test for the Early Detection of Colon Cancer

描述（由申请人提供）：我们的总体目标是开发一种基于尿液DNA的筛查试验，用于早期检测结直肠癌（CRC），该试验是非侵入性的，对患者友好的，并且比现有的非侵入性筛查试验更敏感。尽管有 尽管结肠镜检查是CRC筛查的当前护理标准，但CRC仍然是美国癌症死亡率的第二大原因，因为由于不方便、担心不适和侵入性筛查测试中涉及的风险而导致的低依从性（<40%）。如果在I期诊断，CRC的5年生存率为93%，但如果在IV期诊断，则仅为8%[1，2]。因此 在美国，迫切需要为超过7000万50岁及以上的人增加CRC筛查。目前可用的非侵入性CRC筛查测试包括粪便潜血测试（FOBT），粪便免疫化学测试（FIT），粪便DNA测试（PreGenPlus，Exact Sciences，Maynard，MA），下一代粪便DNA测试和Septin 9血浆测试。不幸的是，成本高、样本收集不方便或这些测试的灵敏度低导致CRC筛查的总体合规率（~60%）不太令人满意。因此，需要一种不那么令人不快、无创、低成本和高灵敏度的筛查试验来提高依从率，并提高晚期腺瘤和CRC的早期发现率，以改善疾病的预后。尿液中含有核酸，可用于早期检测发生在非泌尿道部位的疾病和癌症。我们已经成功地检测到mVIM与CRC患者的尿液中的敏感性为75%，在一个小的试点研究。基于这些数据，我们的mVIM尿液检测已被纳入EDRN 6000-受试者II期验证研究（方案ID 320）。JBS Science Inc.已经进行了初步实验，并建议开发一种JBS CRC尿液检测，检测三种标志物，mVIM和突变的K-ras和BRAF DNA，以确保在盲法预验证研究中至少可以获得70%的检测CRC的灵敏度。JBS科学公司已经证明了这一建议的几个关键领域的可行性。本申请的目标是开发针对K-ras和BRAF突变的稳健检测，并结合用于JBS CRC尿液检测的已开发mVIM检测（目标1），并在开放标签训练集中训练该检测，然后在I期研究中在尿液样本的盲态检测集中验证该检测（目标2）。我们将在一项大型验证研究中进一步开发和评估尿液DNA检测。 公共卫生相关性：目前迫切需要开发一种敏感的，患者友好的，非侵入性的筛查测试，以识别具有CRC高可能性的个体，并将其带到结肠镜检查中进行确认和治疗，因此可以更早地检测到CRC并改善疾病的预后。这个I期项目的目标是通过分析结肠癌相关的遗传和表观遗传修饰来探索尿液DNA检测检测结肠癌早期阶段的能力。

DESCRIPTION (provided by applicant): Our overall goal is to develop a urine DNA-based screening test for the early detection of colorectal cancer (CRC) that is noninvasive, patient-friendly, and more sensitive than existing noninvasive screening tests. Despite the availability of colonoscopy, the current standard of care for CRC screening, CRC remains the nation's second leading cause of cancer mortality because of the low compliance (<40%) due to inconvenience, fear of discomfort, and the risk involved in the invasive screening test. The 5-year survival rate for CRC is 93% if it is diagnosed at stage I but only 8% if diagnosed at stage IV [1, 2]. Thus, the need is urgent to increase CRC screening for more than 70 million people in the United States age 50 and older. Current available noninvasive CRC screening tests include the fecal occult blood test (FOBT), fecal immunochemical test (FIT), the stool DNA test (PreGenPlus, Exact Sciences, Maynard, MA), next generation stool DNA test, and the Septin 9 plasma test. Unfortunately, the high cost, the inconvenience of sample collection, or the low sensitivities of these tests result in an overall less than satisfactory compliance rate (~60%) for CRC screening. Therefore, a less unpleasant, noninvasive, low cost, and highly sensitive screening test is needed to enhance the compliance rate and to increase the rate of early detection of advanced adenoma and CRC to improve the prognosis of the disease. Urine contains nucleic acids that can be used for the early detection of diseases and cancers that occur at non-urinary tract sites. We have successfully detected mVIM in urine of patients with CRC with a sensitivity of 75% in a small pilot study. Based on these data, our mVIM urine test has been included in the EDRN 6000-subject phase II validation study (Protocol ID 320). JBS Science Inc. has performed preliminary experiments and proposes to develop a JBS CRC urine test detecting three markers, mVIM and mutated K-ras and BRAF DNA, to ensure that at least 70% sensitivity to detect CRC can be obtained in a blinded prevalidation study. JBS Science Inc has demonstrated the feasibility of several key areas of this proposal. The goal of this application will be to develop robust assays for K-ras and BRAF mutations combined with a developed mVIM assay for the JBS CRC urine test (Aim 1) and to train this test in an open-label training set and then validate this test in a blinded test set of urine samples (Aim 2) in the phase I study In phase II, we will further develop and evaluate the urine DNA test in a large validation study. PUBLIC HEALTH RELEVANCE: There is an urgent need to develop a sensitive, patient-friendly, noninvasive screening test to identify individuals who have high likelihood of having CRC and bring them to colonoscopy for confirmation and treatment, so CRC can be detected earlier and the prognosis of the disease can be improved. The goal of this phase I project is to explore the ability of a urine DNA test to detect early stages of colon cancer by analyzing colon cancer-associated genetic and epigenetic modifications.