Abstract
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.
Highlights
Despite tremendous advances in the treatment of cancer, colorectal cancer (CRC) remains the second leading cause of cancer-related deaths (Carethers and Doubeni, 2020)
To identify the microsatellite stable (MSS)–related prognostic genes, we developed a pipeline as follows: 1) across the three cohorts, the limma package was applied to perform differential analysis between the non–microsatellite instability-high (MSI-H)/PMMR CRC and MSI-H/ dMMR CRC groups with an FDR < 0.01; the overlap of the three cohorts was defined as MSS-related genes
After controlling for gender; age; T stage, N stage, M stage, and AJCC stage; adjuvant chemotherapy (ACT); tumor mutation burden (TMB); neoantigen; and TP53, KRAS, BRAF, and PIK3CA mutations, microsatellite stable–associated signature (MSSAS) remained statistically significant for predicting the overall survival (OS) in the three cohorts, which suggested that MSSAS was an independent risk factor for the OS (Figures 4A–C)
Summary
Despite tremendous advances in the treatment of cancer, colorectal cancer (CRC) remains the second leading cause of cancer-related deaths (Carethers and Doubeni, 2020). CRC can be divided into mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) and mismatch repair proficient (pMMR)/non–MSI-H tumors (Ganesh et al, 2019; Endo et al, 2020). Chemotherapy alone (5-fluorouracil) or in combination with radiation is the standard treatment for patients with advanced CRC (Maiuthed et al, 2018; Dekker et al, 2019). Non–MSI-H/pMMR CRC has better efficacy for 5-fluorouracil–based chemotherapy, non–MSI-H/ pMMR CRC patients have demonstrated a worse prognosis and higher relapse rate (Lizardo et al, 2020). Immunotherapy has attracted tremendous attention due to its significant effect on solid tumors, including CRC (Liu et al, 2021a). Accumulating evidence has revealed that immunotherapy improves the prognosis of MSI-H/pMMR CRC patients but has no effect on non–MSI-H/pMMR CRC (Biller and Schrag, 2021).
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