KRAS/NRAS/BRAF Mutations and Mismatch Repair Deficiency in Patients with Early-Onset Colorectal Cancer: A Clinicopathological Analysis

Abstract

Background

Early-onset colorectal cancer (CRC) is characterized by distinct molecular and clinical features, a more advanced stage at diagnosis, and unique challenges in clinical management.

Aim

This study aimed to characterize the clinicopathologic features of early-onset CRC and investigate the associations between clinicopathologic characteristics and genetic mutations in young Chinese patients.

Methods

In total, 239 young Chinese patients (age range: 22-45 years) diagnosed with CRC who underwent surgery from January 2016 to June 2022 were retrospectively enrolled. KRAS, NRAS, and BRAF mutations were detected using a mutation analysis panel kit. Mismatch repair (MMR) protein (MLH, PMS2, MSH2, MSH6) expression was evaluated by immunohistochemistry. Pearson's chi-squared test was used to assess the relationships of genetic mutations and MMR with patients’ clinicopathologic characteristics.

Results

The overall KRAS/NRAS/BRAF mutation rate was 50.6% (121/239), including individual rates of 44.4% (KRAS), 2.1% (NRAS), and 4.2% (BRAF). In addition, 15.1% of the patients (36/239) were MMR-deficient (dMMR). The BRAF V600E mutation was significantly associated with high grade (P = .012). Similarly, dMMR status showed significant associations with larger tumor size (P = .028), tumor location (P < .001), the absence of lymph node metastasis (P = .001), and the absence of distant metastasis (P = .038). KRAS mutations were more frequent in dMMR tumors than in MMR-proficient tumors (63.8% vs 40.8%).

Conclusion

Genetic mutations in the RAS/RAF pathway and dMMR status are associated with distinct clinicopathological features in patients with early-onset CRC. dMMR is a potentially favorable prognostic marker.