Critical evaluation of LPCs markers for colorectal cancer

描述（由申请人提供）：结直肠癌（CRC）是美国第三大最常诊断的癌症，也是癌症相关死亡的第二大原因。早期发现结直肠癌的5年相对生存率为90%。然而，只有37%的CRC病例在早期被发现，而出现远处转移的患者的5年生存率仅为8-9%。虽然结肠镜检查的敏感性和特异性值超过95%，但由于成本以及与该检查相关的感知不便和不适，依从性程度较低。因此，许多患者仍然存在晚期和潜在的致命疾病。虽然近年来发展了许多基于血液或粪便的结直肠癌检查，但这些检查都没有结肠镜检查的敏感性和特异性。因此，开发一种简单、无创且高度可靠的早期检测结直肠癌的方法仍然是一个重要的需求。我们发现血浆中几种溶血磷脂酰胆碱（LPCs）水平是CRC的潜在标志物，在我们的试点工作中，我们表明这些标志物对CRC的敏感性和特异性分别为82%和93%。建立可重复性，在完全独立的样本集中重新测试和验证敏感性和特异性的估计是至关重要的，也是绝对必要的，以便批判性地评估这些标记物的临床意义和效用。此外，确定LPCs在腺瘤性息肉中是否发生改变也很重要。我们提出两个目标。首先，我们将在一项完全独立的研究中通过确定LPCs的敏感性和特异性来确定LPCs是否是检测CRC的有效标志物。将分析来自结直肠癌病例和结肠镜阴性对照的174对血液样本。其次，将确定血浆LPCs水平是否为早期结直肠肿瘤和/或疾病进展的标志。我们将确定与结肠镜检查阴性的健康对照组相比，腺瘤性息肉患者（194个样本）的血浆LPCs是否减少，以及LPCs水平是否与腺瘤性息肉的大小和组织病理学相关。这些研究将为评估LPCs的临床应用潜力提供关键信息。公共卫生相关性：结直肠癌（CRC）是美国第三大最常诊断的癌症，也是导致癌症相关死亡的第二大原因。开发一种简单、无创和高度可靠的检测方法来早期发现结直肠癌仍然是一个重要的需求，因为当结直肠癌在早期被诊断出来时，它是可以治愈的。我们发现一组被称为溶血磷脂酰胆碱（LPCs）的脂质化合物可能是早期检测结直肠癌的有用标志物。拟议的研究将在健康对照受试者、腺瘤性息肉患者和结直肠癌患者中严格评估和验证这些标记物。

DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the second leading cause of cancer-related deaths in the United States. When CRC is detected early, the 5-year relative survival rate is 90%. However, only 37% of CRC cases are detected at an early stage and the 5-year survival rate for subjects presenting with distant metastases is only 8-9%. While colonoscopy has reported sensitivity and specificity values exceeding 95%, the degree of adherence is low due to the cost, as well as to perceived inconvenience and discomfort associated with this test. As a result, many patients still present with late-stage and potentially fatal disease. Although many blood- or stool-based tests for CRC have been developed in recent years, none of these tests have sensitivity and specificity similar to those of colonoscopy. Thus, there continues to be an important need for the development of a simple, non-invasive and highly reliable test for the early detection of CRC. We have found that plasma levels of several lysophosphatidylcholines (LPCs) are potential markers for CRC and in our pilot work we show that these markers achieved a sensitivity and specificity of 82% and 93%, respectively for CRC. It is critical and absolutely necessary to establish reproducibility and to retest and validate the estimates for sensitivity and specificity in completely independent sample sets in order to critically evaluate the clinical significance and utility of these markers. In addition, it is important to determine whether LPCs are changed in adenomatous polyps. We propose two aims. First, we will determine whether LPCs are effective markers for detecting CRC by determining their sensitivity and specificity in a totally independent study. 174 pairs of blood samples from CRC cases and colonoscopic negative controls will be analyzed. Secondly, will will determine whether plasma levels of LPCs are markers for early colorectal neoplasia and/or disease progression. We will determine whether plasma LPCs are reduced in subjects with adenomatous polyps (194 samples), as compared to colonoscopically negative healthy controls, and whether the levels of LPCs correlate with the size and histo-pathology of adenomatous polyps. These studies will provide critical information to evaluate the potential of LPCs' clinical usage. PUBLIC HEALTH RELEVANCE: Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the second leading cause of cancer-related deaths in the United States. There continues to be an important need for the development of a simple, non-invasive and highly reliable test for the early detection of CRC, since when CRC is diagnosed at an early stage, it is curable. We have found that a group of lipid compounds called lysophosphatidylcholines (LPCs) may represent useful markers for the early detection of CRC. The proposed studies will critically evaluate and validate these markers in healthy control subjects, patients with adenomatous polyps, and patients with colorectal cancers.