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

项目总结 结直肠癌(CRC)筛查的有效性，同时也增加了对检测的重视 即使是最小的腺瘤，也带来了新的临床挑战。越来越多的人 被确认为有腺瘤性息肉，这是结直肠癌的良性先兆。这些病人是 建议接受监测，或重复结肠镜检查以监测复发。指导方针 对于基于息肉大小和病理分类的监测间隔，不能准确反映 结直肠癌进展的个体风险。由于缺乏可靠的标记物来对个别患者的癌症进行分层 腺瘤切除后的风险监测结肠镜在临床实践中经常被不恰当地使用。 临床医生迫切需要性价比高的测试来准确区分需要更多治疗的高危患者 来自低危患者的频繁监测，监测间隔可以延长。建立在 基于光谱域光学相干层析成像(SD-OCT)的成像原理，我们开发了一种 常规组织活检三维纳米尺度核构图(3D-NanNAM)的新方法 为患者的临床护理而获得。我们已经证明了纳米NAM直接量化了亚微观 未染色福尔马林固定石蜡切片中细胞核固有三维结构的改变 具有纳米级敏感性的嵌入式(FFPE)组织切片。该项目的目标是开发一种可靠的 与结直肠癌进展相关的纳米NAM标记的风险分类，并严格验证其 在结直肠腺瘤的情况下持续预测CRC进展风险的能力。我们将严格执行 用动物验证3D纳米NAM标志物在肠道肿瘤发生中的致癌依赖性 模型，并描述其在加速和抑制肿瘤形成过程中的相应变化。 我们还将评估纳米NAM标志物在预测晚期腺瘤复发风险方面的应用。 该项目的成功将验证用于CRC进展的NanNAM标记-风险并证明未来更大- 使用纳米NAM作为客观的、个性化的分层工具来指导的规模临床研究 建立监视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.