SOX9 Expression in Colorectal Adenomas Improves Surveillance Colonoscopy Risk Stratification in a Bowel Screening Population

Objectives Adenomas are known precursors to colorectal cancer (CRC). Current UK post-polypectomy surveillance guidelines use polyp size, numbers, and histology to stratify the risk of patients developing metachronous polyps or CRC. However, these risk guidelines suffer from poor predictive value, often leading to under/over surveillance. Design Adenomas removed from 1257 patients at bowel screening colonoscopy were retrospectively identified to investigate mutational profile and protein expression trends associated with the detection of metachronous polyps or CRC. The presence or absence of metachronous polyps or CRC was recorded 6 months to 6 years after index polypectomy. Results APC and KRAS were the most mutated genes in these patients (87% and 34% respectively), and both were significantly co-occurring with the 6th most mutated gene SOX9 (17% co-occurring with APC, p=0.047; 23% co-occurring with KRAS, p=0.012). High SOX9 cytoplasmic expression was significantly associated with the detection of metachronous polyps or CRC (HR 1.543, p=0.001) and improved high risk stratification when combined with BSG2020 guidelines versus guidelines alone (HR 2.626, p<0.0001). High cytoplasmic SOX9 alone and in combination with current guidelines was an independent predictor of metachronous polyps or CRC according to various regression models. This was validated in an independent test dataset, where high cytoplasmic expression was significantly associated with the detection of metachronous polyps or CRC (HR 1.654, p=0.012) and enhanced risk stratification when combined with BSG2020 guidelines versus guidelines alone (HR 2.473, p=0.0018). Conclusion High cytoplasmic SOX9 expression within adenomas is associated with shorter time to detection of metachronous polyps or CRC.