Tumour location and mismatch repair status impact gene expression profiles associated with lymph node metastases in T1 colon cancers

Accurate identification of which patients with early (T1) colon cancer (CC) have lymph node metastases (LNM) is a major challenge. Current strategies have limited accuracy, resulting in overtreatment of > 80% of patients. Whilst gene expression profiles (GEPs) have shown promise in identifying patients with LNM in early studies, these have not become a routine part of clinical practice. A limitation of these GEPs is that they are generic and so agnostic of other factors that could influence gene expression, such as tumour location and mismatch repair (MMR) status. In a retrospective translational study of 24 patients who underwent surgery for T1 CC, we demonstrate that both tumour location and MMR status have a significant impact on intratumoural gene expression. This impact was seen in patients with and without LNM. When compared to analyses of all patients, side-specific and MMR status-specific analyses revealed a higher number of differentially expressed genes with lower false discovery rates. Several interesting candidate genes for LNM were identified, including AHNAK, ATG12 and DMBT1. These findings demonstrate the influence of tumour location and MMR status on intratumoural gene expression in T1 CC and highlights the need to account for these factors when developing GEPs for clinical translation.