KRAS, NRAS and BRAF Mutational Landscape in Serbian Early-Onset Colorectal Cancer Patients

IntroductionEarly-onset colorectal cancer (EOCRC) is increasing worldwide, with Serbia showing a similar incidence compared to global trends. Precise mutation genotyping has gained importance following the recent approval of KRAS-specific inhibitors. Although KRAS, NRAS, and BRAF testing is routinely performed in Serbia, specific mutation subtypes in EOCRC patients have not yet been published. This retrospective cohort study aimed to investigate temporal trends in EOCRC incidence in Serbia and characterize the mutational profile of KRAS, NRAS, and BRAF in EOCRC patients.MethodsNational cancer registry data from 2016 to 2022 were analyzed to assess EOCRC incidence trends. Molecular testing for KRAS, NRAS, and BRAF was performed on 681, 420, and 67 EOCRC patients, respectively, using qPCR-based diagnostic assays, complemented by Sanger sequencing on 54 cases to characterize KRAS exon 2 and BRAF V600E mutations.ResultsRegistry data revealed a consistent upward trend in EOCRC incidence, especially in the 45-49 years' age group. In the qPCR-tested cohort, KRAS mutations were detected in 44.3% (302/681), NRAS in 6.4% (27/420), and BRAF in 8.9% (6/67). In the sequenced subset, KRAS mutations were found in 20.4%, including G12D (36.4%), G13D (27.3%), G12 C (18.1%), and G12S/G12 V (9.1%) variants. BRAF V600E was detected in 3.7%.ConclusionsWe report a rise in EOCRC in Serbia, especially in ages 45-49, and recommend policy makers to lower the screening age to 45. We present the first detailed molecular profile of Serbian EOCRC and recommend that policy makers implement routine KRAS variant testing and ensure access to KRAS G12C-targeted therapies to improve personalized care.