Integrated Molecular Profiling of Colorectal Cancer by Tumor Location: Evidence from a Real-World Cohort with Primary and Metastatic Samples

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Abstract
Background/Objectives: Colorectal cancer (CRC) shows significant molecular diversity influenced by tumor location. Right- and left-sided CRCs differ in terms of microsatellite instability (MSI), mutational burden, and actionable biomarkers. This study aimed to characterize the clinicopathological and molecular features of CRC stratified upon tumor location. Methods: A consecutive series of CRC cases was retrospectively analyzed. Tissue samples were obtained from primary tumors (71%) or metastatic lesions (29%). All cases were evaluated by histopathology, immunohistochemistry (IHC), and targeted next-generation sequencing (NGS). Tumor location was assigned based on the primary tumor (43 right-sided and 35 left-sided cases). Results: Right-sided CRCs were more frequent in older patients and females and showed higher rates of deficient MMR (42% vs. 17%, p = 0.02), MSI-H (39% vs. 14%, p = 0.02), and high tumor mutational burden (TMB-high, ≥10 Mutations/Mb, 56% vs. 28%, p = 0.02). The most frequent pathogenic class 5 mutations were TP53 (65%), APC (49%), and KRAS (44%). APC was the most frequently mutated gene in both pathogenic (class 5) and likely pathogenic (class 4) categories, with class 5 variants more common in left-sided tumors and class 4 variants predominating in right-sided tumors. BRAF mutations showed a statistically significant trend toward higher frequency in right-sided tumors (p = 0.05). HER2/neu overexpression (3+) was seen in 15% of patients, exclusively in MSS left-sided tumors. PD-L1 expression (CPS ≥ 1) was detected in 20% of patients, irrespective of location, and pan-TRK IHC was negative in all cases. The 29% of samples derived from metastatic lesions were predominantly MSS/pMMR (87%). Conclusions: Tumor location in CRC correlates with distinct molecular patterns. Right-sided tumors are associated with dMMR, MSI-H, and higher TMB, while left-sided CRCs display more ERBB2 alterations and class 5 APC mutations. The results highlight the importance of integrating tumor location into personalized molecular diagnostics and therapeutic planning for CRC patients.
Funding Information
  • German Federal Armed Forces (45K3-S-54-2224)

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