Comprehensive genomic and clinicopathologic characterization of <i>KRAS</i> G12C– and other <i>KRAS</i> G12–mutated non-colorectal gastrointestinal malignancies.

Abstract

e16486 Background: Allele-specific KRAS G12C inhibitors have revolutionized lung and colorectal cancer treatment, yet the biology of G12C in other gastrointestinal (GI) malignancies remains undefined. We aimed to elucidate the clinicopathologic and genomic landscape of KRAS G12C-mutated tumors compared to other G12 variants in a large non-colorectal GI cohort. Methods: We queried cBioPortal for pancreatic, esophagogastric, hepatobiliary, ampullary, and appendiceal adenocarcinomas. Following data quality control, the final cohort (n = 6,352) was stratified into KRAS wild-type (n = 3,293), G12C (n = 63), and other G12 variants (n = 2,996). Clinicopathologic features, tumor mutational burden (TMB), microsatellite instability status, and co-alteration in 96 key genes across 11 signaling pathways were compared. Statistical significance was assessed using Fisher’s exact or Chi-square tests for categorical variables and Kruskal-Wallis tests for continuous variables. The Benjamini-Hochberg method was applied to correct for multiple hypothesis testing. Results: KRAS G12C prevalence was 1.0% overall, with significant heterogeneity across cancer subtypes (p &lt; 0.001). Appendiceal adenocarcinoma demonstrated the highest G12C prevalence at 5.71% (10/175), followed by ampullary (1.44%, 2/139), pancreatic (1.17%, 34/2906), hepatobiliary (0.88%, 12/1360), and esophagogastric cancers (0.28%, 5/1772). G12C patients were significantly older than wild-type patients (64.8±11.2 vs 62.5±12.9 years, mean±SD, p &lt; 0.001) but younger than other G12 variant carriers (65.8±10.4 years). G12C tumors demonstrated intermediate genomic instability, with a TMB of 4.82±6.17 compared to 4.98±10.55 in wild-type tumors and 3.67±10.12 in other G12 variants (p &lt; 0.001). Notably, G12C tumors were universally microsatellite stable (0% MSI-H vs 4.0% wild-type vs 0.9% other G12, p &lt; 0.001). Genomic analysis revealed that AKT1 mutations were significantly enriched in the G12C cohort (6.3% vs 0.4%; q = 0.025) as compared to other G12 variants. A trend of increased mutation frequency in HRAS was observed specifically in pancreatic cancers in G12C tumors as compared to other variants (8.8% vs 0.7%; q = 0.083). In pancreatic adenocarcinoma, G12C tumors were enriched for chromatin modifiers, notably ARID1A (17.6% vs 7.7%, p = 0.045) and SETD2 / SETD26 (8.8% vs 1.1%, p = 0.006), though these did not reach FDR significance. Notably, the immunotherapy-resistance drivers STK11 and KEAP1 were absent (0%) in the whole G12C cohort. Conclusions: KRAS G12C represents a biologically distinct subgroup of exon 2 KRAS mutations compared to other KRAS G12 pathogenic variants. The absence of resistance markers and enrichment of actionable AKT1 and chromatin-modifier mutations suggest distinct therapeutic vulnerabilities in non-colorectal KRAS G12C-mutated GI cancers.