Abstract C020: Novel insights from the investigation of experimental mutational signatures in early-onset colorectal cancer and colonic polyps

Abstract Introduction: Profiling colorectal cancers (CRCs) for tumor mutational signatures (TMS) offers new opportunities to characterize molecular subtypes. Recently, COSMIC published a comprehensive set of experimental mutational signatures that directly link specific environmental exposures to mutational patterns observed in human cancers. Environmental exposures are recognized as major contributors to CRC development and have been hypothesized to drive the recent rise in early-onset CRC (EOCRC), but the molecular fingerprints of these exposures in EOCRCs have not been systematically characterized. Methods: We performed whole exome sequencing (WES) on tumor and matched blood-derived DNA from 324 non-hereditary, mismatch repair proficient early-onset samples (diagnosed 55 years of age) comprising 277 CRCs and 47 pre-malignant polyps. Mutational signatures were calculated using a novel approach that combined COSMIC v3. 4 signatures previously observed in CRC (n=26) and a curated set of experimental mutational signatures (n=50). Environmental signatures were filtered to human iPSC-derived signatures, excluding those with a negative AMES test, those marked as controls, and signatures not seen previously in CRC. Signature definitions with 95% cosine similarity were merged. Results: On average, 24. 7% ± 10. 1% (mean ± s. d, range 0. 1%-60. 1%) of somatic mutations were assigned to environmental signatures. Across the cohort, 14% (46/324) exhibited a dominant environmental signature, with N-nitrosopyrrolidine being the most prevalent (6. 2%, 20/324). Premalignant lesions showed higher rates of dominant environmental signatures (21%, 10/47) compared to invasive cancers, suggesting environmental exposures may be a key component in early carcinogenesis. Conclusions: This study provides a comprehensive view of the landscape of mutational processes in non-hereditary mismatch repair proficient EOCRC and early-onset polyps through assessment of both tumor mutational signatures and experimental mutational signatures. Environmental exposures represent a significant component of the mutational landscape in early-onset colorectal neoplasia, with enhanced prevalence in premalignant lesions. These findings support the likely role of environmental drivers in the rising incidence of EOCRC. Citation Format: Peter Georgeson, Alysha Prisc, Jihoon Joo, Khalid Mahmood, Romy Walker, Mark Clendenning, Julia Como, Natalie Diepenhorst, Julie McDonald, Steven Gallinger, Robert Grant, Dylan E. O’Sullivan, Darren R. Brenner, Finlay Macrae, Christophe Rosty, Ingrid M. Winship, Mark A. Jenkins, Daniel D. Buchanan. Novel insights from the investigation of experimental mutational signatures in early-onset colorectal cancer and colonic polyps abstract. In: Proceedings of the AACR Special Conference in Cancer Research: The Rise in Early-Onset Cancers—Knowledge Gaps and Research Opportunities; 2025 Dec 10-13; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2025;31 (23Suppl): Abstract nr C020.