Comprehensive analysis of KRAS aberrations in pan-cancer, with a focus on prognostic and therapeutic implications

Background: KRAS is one of the most frequently mutated oncogenes in humans. KRAS aberrations play a significant role in various solid tumors, affecting patient prognosis and treatment outcomes. Objectives: We identified features of genetic alterations in KRAS, including single amino acid substitutions and amplifications, based on the results of next-generation sequencing tests in 1667 advanced solid tumor patients. Design: Retrospective cohort study. Methods: Among 1667 patients, 28.1% (N = 468) had KRAS aberrations (single-nucleotide variant (SNV): N = 438, 26.1%; amplification (copy number variation): N = 48, 2.9%) in metastatic solid tumors. Results: The incidence rate of SNVs was higher in pancreatic cancer (N = 89, 89.9%) than in other tumors, including colorectal cancer (N = 259, 47.3%) and small bowel cancer (N = 4, 40.0%). Most of the mutations were missense mutations (N = 434, 99.1%). In addition, we examined the specific location of SNVs; the mutational type G12D (N = 178, 40.6%) was the most frequent, followed by G12V (N = 95, 21.7%) and G13D (N = 47, 10.7%). In the survival analysis, the mutational types of G12V and G13D influenced the poor survival of patients (G12V, the mutant type; 245 vs the wild type; 531 days; G13D, the mutant type; 435 vs the wild type; 531 days). Conclusion: In patients with KRAS amplification, the copy number range varied among the tumor types. Bladder cancer (147.9), cholangiocarcinoma (16.2), and gastric cancer (11.0) had relatively high median copy numbers of KRAS. Overall, our data are expected to provide valuable information for patients with various metastatic solid tumors and KRAS aberrations.