Gene Expression Profile Reveals a Prognostic Signature of Non-MSI-H/pMMR Colorectal Cancer

Studies have demonstrated that non-MSI-H/pMMR colorectal cancer (CRC) has a worse prognosis and relapse rate than microsatellite instability-high (MSI-H)/mismatch repair deficient (dMMR) CRC. Hence, searching for a novel tool to advance the prognostic management of non-MSI-H/pMMR CRC is vital. In this study, using three independent public cohorts and a clinical in-house cohort, we developed and validated a microsatellite stable-associated signature (MSSAS). The initial signature establishment was performed in GSE39582 (n = 454). This was followed by independent validation of this signature in The Cancer Genome Atlas-CRC (n = 312), GSE39084 (n = 54), and in-house cohort (n = 146). As a result, MSSAS was proven to be an independent risk factor for overall survival and relapse-free survival in non-MSI-H/pMMR CRC. Receiver operating characteristic analysis showed that MSSAS had a stable and accurate performance in all cohorts for 1, 3, and 5 years, respectively. Further analysis suggested that MSSAS performed better than age, gender, and the T, N, M, and AJCC stages, adjuvant chemotherapy, tumor mutation burden, neoantigen, and TP53, KRAS, BRAF, and PIK3CA mutations. The clinical validation was executed to further ensure the robustness and clinical feasibility of this signature. In conclusion, MSSAS might be a robust and promising biomarker for advancing clinical management of non-MSI-H/pMMR CRC.

Automated summary

The study developed a novel microsatellite stable-associated signature (MSSAS) and demonstrated its independent prognostic value in non-MSI-H/pMMR CRC patients for overall survival and relapse-free survival, showing stable and accurate predictive performance across multiple cohorts and outperforming other clinical indicators. Clinical validation further supported the robustness and clinical feasibility of MSSAS as a promising biomarker for advancing the management of non-MSI-H/pMMR CRC.