Data from Mutational Analysis of Early, Low-Grade Bowel Polyps Defines a Subgroup with Concurrent, High-Risk Oncogenic Drivers Independent of Polyp Size

Abstract The accumulation of pathogenic mutations in premalignant colorectal neoplasms is critical for colorectal cancer development; however, the frequency and diversity of pathogenic driver mutations in early-stage colorectal polyps is incompletely known. We investigated this by whole-exome sequencing of low-grade dysplasia (LGD) colorectal polyps and paired germline DNA. Interestingly, in these early lesions, there was no association with mutational burden and the known risk factor of polyp size (range, 3–15 mm). However, a subset of LGD polyps harbored concurrent, oncogenic alterations in colorectal cancer–causing pathways of WNT/β-catenin, p53, or RTK-RAS. Further analysis suggested that the concurrent mutation signature was associated with increased polyp burden. Spatial transcriptomic analysis revealed that immune effectors, including NF-κB signaling, were a characteristic of LGD polyps with concurrent pathogenic mutations. Together, these observations suggest that some small-sized, early colorectal neoplasms have enhanced oncogenic potential and highlight that nonadvanced colorectal adenoma may not be universally considered a low-risk finding. Significance: Through whole-exome sequencing of early colorectal polyps characterized by LGD, we demonstrate that polyp size poorly correlates with mutational burden. Some small-sized (<10 mm polyps) early polyps harbored concurrent driver gene mutations commonly seen in adenocarcinoma. Sequencing of key driver genes in early polyps may identify risky lesions that cannot be detected by histology alone.