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

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.