Mutational profile of colorectal cancer cells in patients with multiple primary cancers.

Abstract

e15538 Background: Colorectal cancer (CRC) is one of the three most common malignancies and a frequent component of multiple primary cancers (MPCs). The molecular mechanisms driving the development of MPCs remain incompletely understood. This study aimed to investigate the mutational landscape of CRC occurring within the context of MPCs. Methods: The study included 450 patients with single primary CRC (sCRC) and 62 patients with synchronous or metachronous MPCs involving CRC. DNA was isolated from formalin-fixed, paraffin-embedded tumor tissues. All samples were analyzed for KRAS , NRAS , and BRAF mutations, as well as microsatellite instability (MSI) status. A subset of MPCs cases underwent targeted high-throughput next-generation sequencing (NGS). Bioinformatics tools were used for data analysis. Results: No significant differences in gender, age, or histological type were observed between the MPCs and sCRC groups. The frequency of the KRAS G12A mutation was significantly higher in the MPCs group (17.7%, n = 11) compared to the sCRC group (p < 0.0001; OR = 15.96; 95% CI [5.66–44.98]). A relative predominance of MSI-high status was also found in the MPCs group (p < 0.04; OR = 2.32; 95% CI [1.004–5.37]). Targeted NGS of CRC samples from the MPCs cohort revealed 109 genetic variants across 16 of the 32 genes analyzed. The most commonly mutated genes were TP53 , KRAS , PIK3CA , APC , and BRAF , predominantly involving missense and nonsense mutations. Conclusions: This study demonstrates that CRC arising as part of MPCs has a distinct molecular profile, characterized by a higher prevalence of specific KRAS mutations and MSI-high status. These findings provide a basis for further research into the molecular pathogenesis of MPCs, which may inform the development of improved treatment and surveillance strategies.