Three dimensional nanoscale nuclear architecture mapping based taxonomy of precursor lesions for predicting colorectal cancer risk

项目摘要 结直肠癌（CRC）筛查的有效性，同时越来越重视检测 即使是最小的腺瘤，也带来了新的临床挑战。越来越多的人 被鉴定为含有腺瘤性息肉，是CRC的良性前体。这些患者 建议进行监测，或重复结肠镜检查以监测复发。准则 基于息肉大小和病理分类的监测间隔不能准确反映 个体CRC进展的风险。由于缺乏可靠的标记物来对个体患者的癌症进行分层， 腺瘤切除术后的风险，监测结肠镜往往在临床实践中应用不当。 临床医生迫切需要具有成本效益的测试，准确区分需要更多的高风险患者 对低风险患者进行频繁监测，可延长监测间隔。基础上 成像原理背后的谱域光学相干断层扫描（SD-OCT），我们已经开发了一种 常规组织活检的3D纳米级核结构映射（3D-nanoNAM）新方法 用于患者的临床护理。我们已经证明，nanoNAM直接量化亚微观 在未染色的福尔马林固定的石蜡切片中， 包埋（FFPE）组织切片具有纳米级的灵敏度。该项目的目标是开发一种可靠的 与CRC进展相关的nanoNAM标志物的风险分类，并严格验证其 在结直肠腺瘤的背景下，一致预测CRC进展风险的能力。我们将严格 使用动物验证3D nanoNAM标志物在肠肿瘤发生中的致癌依赖性 模型，并表征其在肿瘤发生的加速和抑制过程中的相应变化。 我们还将评估使用nanoNAM标记物来预测晚期腺瘤的复发风险。 该项目的成功将验证nanoNAM标记物用于CRC进展风险，并证明未来更大的 采用nanoNAM作为客观的、个性化的分层工具， 建立监测结肠镜检查的推荐时间间隔。

PROJECT SUMMARY The effectiveness of colorectal cancer (CRC) screening, with a concomitant increased emphasis on detection of even the smallest adenomas, has resulted in a new clinical challenge. An increased number of people are being identified as harboring an adenomatous polyp, the benign precursor to CRC. These patients are recommended to undergo surveillance, or repeated colonoscopy for monitoring for recurrence. The guidelines for surveillance intervals, based on polyp size and pathologic classification, do not accurately reflect individual’s risk for CRC progression. Due to the lack of reliable markers to stratify individual patient’s cancer risk after adenoma resection, surveillance colonoscopy is often improperly applied in clinical practice. Clinicians urgently need cost-effective tests that accurately distinguish high-risk patients in need of more frequent surveillance from low-risk patients for whom surveillance interval can be lengthened. Building on the imaging principle behind Spectral-Domain Optical Coherence Tomography (SD-OCT), we have developed a new approach for 3D nanoscale nuclear architecture mapping (3D-nanoNAM) on tissue biopsies routinely obtained for patients’ clinical care. We have shown that nanoNAM directly quantifies sub-microscopic alterations in the intrinsic 3D structural architecture of cell nuclei in unstained formalin-fixed, paraffin- embedded (FFPE) tissue sections with nanoscale sensitivity. The goal of this project is to develop a reliable risk taxonomy of nanoNAM markers that are associated with CRC progression, and rigorously validate their ability to consistently predict CRC progression risk in the context of colorectal adenoma. We will rigorously validate the carcinogenesis dependence of 3D nanoNAM markers in intestinal tumorigenesis using animal models and characterize their corresponding change during the acceleration and inhibition of tumorigenesis. We will also evaluate the use of nanoNAM markers to predict the recurrence risk of advanced adenomas. Success of this project will validate nanoNAM markers for CRC progression-risk and justify a future, larger- scale clinical study for employing nanoNAM as an objective, personalized stratification tool to guide establishment of the recommended time interval for surveillance colonoscopy.