Distinct Molecular and Prognostic Profiles of Left- and Right-Sided Colorectal Cancer Revealed by NGS Analysis: The Role of SMAD4 and SETD2 Mutations.

BACKGROUND: Colorectal cancer (CRC) isthe third most common cancer and the second leading cause of cancer-relateddeath worldwide. Its genetic heterogeneity complicates treatment. This studyaimed to compare clinicopathological, molecular, and prognostic factors betweenleft-sided (LCC) and right-sided (RCC) CRC. METHODS: We retrospectively analyzed 48 CRCpatients who received next-generation sequencing (NGS) of tumor tissue andmatched leukocytes using a 425-gene panel. Clinicopathological, molecular, andprognostic factors were compared between LCC and RCC. RESULTS: RCC exhibited a higher frequencyof BRAF mutations (33.3% vs. 7.1%, p = 0.042) and more frequent alterations in PI3K (p = 0.033), homology-dependent recombination (HDR, p = 0.018), and mismatch repair (MMR, p = 0.002) pathways than LCC. Multivariate analysis identified SMAD4 mutation as an independentpredictor of worse overall survival (OS) (HR = 3.88, 95% CI 1.05-14.29, p = 0.042), which was confirmed in an external cohort of 1796 CRCpatients. In subgroup analyses, SETD2 mutationswere associated with poor prognosis in LCC (HR = 2.20, 95% CI 0.80-6.06, p = 0.026), while ARID1A (p = 0.040) and PRDM1 (p = 0.021) mutations correlated with shorter progression-free survival in RCC. Patients harboring both SMAD4 and SETD2 mutationshad the shortest OS (median: 17.7 months, p < 0.0001). CONCLUSIONS: These findings reveal criticalmolecular and prognostic differences between LCC and RCC and highlight SMAD4 and SETD2 asimportant prognostic biomarkers, suggesting the potential value of location-and mutation-guided precision therapies in CRC.