Structure and function related biomarkers and computational models for predicting adenoma recurrence in patients with advanced adenomas

Colorectal Cancer (CRC) is the fourth most common cancer and second leading cause of cancer death in the U.S., with a troubling increasing incidence rate in younger adults. CRC primarily develops from precancerous adenomatous or serrated polyps. Randomized trials have demonstrated that removing these precursor lesions via colonoscopy can prevent subsequent incident CRC. About 7-10% of individuals undergoing colonoscopy have advanced adenomas (AA), defined by size and histologic characteristics. AAs have a higher risk of evolving to CRC and patients with AA have a 3-fold higher rate of subsequently developing CRC compared to those with normal colonoscopy or non-advanced polyps. About 15 million colonoscopy exams/year are performed in U.S., and 25% of them are done for surveillance, or follow up for a history of adenomas. All individuals with AA are recommended to return in 3 years for repeat examination. This recommendation classifies all AA as having similar risk, but the classification of AA is based on endoscopic assessment of polyp size, or villous or dysplasia characteristics on pathologic review, criteria which are subject to interobserver variability. Detailed molecular correlates to define risk are not employed. Robust biomarkers and reliable computational methods for predicting adenoma recurrence in patients with AA based on accurately defined risk could improve patient outcome by personalizing timing of surveillance exams and potentially reducing subsequent CRC incidence, while also optimizing resource allocation and reducing costs. These biomarkers also have the potential to help identify new and effective prevention treatment. We have developed two novel approaches to evaluate colorectal lesions:1. evaluation of aberrant alterations in chromatin structure at nanoscale sensitivity; and 2. spatial analysis of the molecular and cellular diversity of AA microenvironments. We aim to apply these methods to a set of AA tissues from 240 patients whose longitudinal outcome for adenoma recurrence has been tracked Aberrant chromatin remodeling has been shown to be causally linked to neoplastic development. We hypothesize that capturing this remodeling in the index AA has the potential to serve as a sensitive and specific marker of adenoma recurrence risk in individuals post polypectomy. Additionally, the colorectal microenvironment, through its cell-specific molecular mechanisms of interaction is an active sensor of neoplastic transformation. We hypothesize that a microenvironment pre-cancer atlas of AA that leverages the degrees-of-freedom of these interactions can be utilized for developing functional biomarkers that correlate with adenoma recurrence and CRC risk and identify the likely mechanism driving the risk in individual patients who underwent AA polypectomy In Aim 1 we will develop aberrant chromatin organization as a biomarker for predicting adenoma recurrence in patients with AA. In Aim 2 we will generate the molecular and cellular pre-cancer spatial atlas of AA microenvironment at single cell resolution. Together, this multi-scale – chromatin and microenvironment – interrogation offers a promising opportunity to characterize biological determinants of AA risk and to prevent its recurrence and CRC incidence. Project Number: 1R21CA299788-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Shikhar Uttam | Institution: UNIVERSITY OF PITTSBURGH AT PITTSBURGH, PITTSBURGH, PA | Award Amount: $396,799 | Activity Code: R21 | Study Section: Special Emphasis Panel[ZRG1 BTC-P (80)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11283790