Spectral Markers for Early Detection of Colon Neoplasia

描述(申请人提供)：虽然结肠镜检查被证明可以降低结直肠癌(CRC)的死亡率，但其费用、并发症和有限的可获得性使其不适用于普通人群筛查。通过评估结肠癌发生的“场效应”进行风险分层可以用来确定是否需要结肠镜检查；然而，目前的标志物(例如远端结肠腺瘤性息肉)显然是不够的。Backman博士的团队和同事率先开发了光散射技术来检测发育不良细胞(自然2000和自然医学2001)，现在已经开发出四维光散射指纹(4D-ELF)，这使得能够对纳米尺度的细胞结构进行定量分析。使用4D-ELF，我们在组织学上正常的粘膜中发现了先于实验性结直肠癌所有常规生物标记物的光谱标记物(胃肠病学2004)。评估未受累直肠黏膜的4D-ELF信号对肿瘤的未来发生具有前所未有的敏感性和阳性预测值(&gt；98%)。初步的人体研究证实了这些新型生物标记物的前景。我们建议在结肠镜检查中使用与内窥镜兼容的4D-ELF探针来进一步验证这些光谱标记。基于500名患者的直肠4D-ELF分析，我们将制定晚期息肉/癌症发生和肿瘤排除的预测规则(从而确定不需要进一步筛查的亚组)。我们将在750名患者中前瞻性地测试这些规则。此外，我们将使用遗传性非息肉病、结直肠癌和家族性腺瘤性息肉病作为范例，研究4D-ELF无与伦比的敏感性是否可以检测到由遗传易感性产生的长期CRC风险。我们将评估光谱标记识别突变和预测表型呈现的能力。将来，在直肠检查中可以用4D-ELF探头检测这些光谱标志物，从而为确定最佳的CRC筛查方案提供一种实用而准确的手段。

DESCRIPTION (provided by applicant): While colonoscopy is proven to decrease colorectal cancer (CRC) fatalities, its expense, complications and limited availability makes it impractical for general population screening. Risk-stratification through assessment of the "field effect" of colon carcinogenesis can be used to determine the need for colonoscopy; however current markers (e.g. distal colonic adenomatous polyp) are clearly inadequate. Dr. Backman's group and colleagues, having pioneered light-scattering technologies for detecting dysplastic cells (Nature 2000 & Nature Med 2001), now have developed four-dimensional light-scattering fingerprinting (4D-ELF), which enables quantitative analysis of nano-scale cellular architecture. Using 4D-ELF, we discovered spectral markers in histologically normal mucosa that preceded all conventional biomarkers of experimental CRC (Gastroenterology 2004). Evaluating 4D-ELF signatures from the uninvolved rectal mucosa had unprecedented sensitivity and positive predictive value (>98%) for the future occurrence of neoplasia. Pilot human studies confirmed the promise of these novel biomarkers. We propose to further validate these spectral markers by using an endoscopically-compatible 4D-ELF probe during colonoscopy. Based on rectal 4D-ELF analysis from 500 patients, we will formulate prediction rules for both the occurrence of advanced polyps/cancers and the exclusion of neoplasia (thus identifying a subgroup not requiring further screening). We will prospectively test these rules in 750 patients. Furthermore, we will use hereditary nonpolyposis colorectal cancer and familial adenomatous polyposis as a paradigm to investigate whether the unparalleled sensitivity of 4D-ELF may detect long-term CRC risks engendered by an inherited predisposition. We will evaluate the ability of spectral marker to both identify mutations and forecast phenotypic presentation. In the future these spectral markers may be assayed with a 4D-ELF probe during rectal examination, thus providing a practical and accurate means of determining the optimal CRC screening regimen.