A recurrence‐predictive model based on eight genes and tumor mutational burden/microsatellite instability status in Stage II/III colorectal cancer

Abstract

AbstractBackgroundAlthough adjuvant chemotherapy (ACT) is widely used to treat patients with Stage II/III colorectal cancer (CRC), administering ACT to specific patients remains a challenge. The decision to ACT requires an accurate assessment of recurrence risk and absolute treatment benefit. However, the traditional TNM staging system does not accurately assess a patient's individual risk of recurrence.MethodsTo identify recurrence risk‐related genetic factors for Stage II/III CRC patients after radical surgery, we conducted an analysis of whole‐exome sequencing of 47 patients with Stage II/III CRC who underwent radical surgery at five institutions. Patients were grouped into non‐recurrence group (NR, n = 24, recurrence‐free survival [RFS] > 5 years) and recurrence group (R, n = 23, RFS <2 years). The TCGA‐COAD/READ cohort was employed as the validation dataset.ResultsA recurrence‐predictive model (G8plus score) based on eight gene (CUL9, PCDHA12, HECTD3, DCX, SMARCA2, FAM193A, AATK, and SORCS2) mutations and tumor mutation burden/microsatellite instability (TMB/MSI) status was constructed, with 97.87% accuracy in our data and 100% negative predictive value in the TCGA‐COAD/READ cohort. For the TCGA‐COAD/READ cohort, the G8plus‐high group had better RFS (HR = 0.22, p = 0.024); the G8plus‐high tumors had significantly more infiltrated immune cell types, higher tertiary lymphoid structure signature scores, and higher immunological signature scores. The G8plus score was also a predict biomarker for immunotherapeutic in advanced CRC in the PUCH cohort.ConclusionsIn conclusion, the G8plus score is a powerful biomarker for predicting the risk of recurrence in patients with stage II/III CRC. It can be used to stratify patients who benefit from ACT and immunotherapy.