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.

This project is significant to the public health issue that an increased number of patients are detected with adenomatous polyps, a precursor lesion of colorectal cancer, during colonoscopy screening. These patients are often placed on surveillance colonoscopy, or repeated colonoscopy to monitor the recurrent adenoma. Our proposed project will advance our understanding of nanoscale nuclear architecture in early-stage colon cancer progression in adenoma lesions and our imaging system may serve as a cost-effective and accurate tool for personalized cancer risk prediction to guide efficient utilization of surveillance colonoscopy.