Abstract 5336: Distinct <i>KRAS</i> mutation codons differentially associate with microsatellite instability in colorectal carcinoma.

Abstract Background: MSI/MMR and KRAS are key biomarkers in colorectal carcinomas (CRC) for PD1 inhibitors, EGFR mAbs, and KRAS G12C inhibitors. MSI High is reported to be less common in KRAS mutant CRC. However, because KRAS mutation location influences protein function and CRC pathophysiology, we hypothesized that MSI also differs by KRAS mutation site. Methods: MSI High prevalence was assessed by KRAS mutation location in CRCs using logistic regression in 2 databases: MSK-CHORD, and Caris CODEai. BRAF V600E CRCs were excluded. Results: In MSK-CHORD’s 4,805 CRCs (nonBRAF V600E, NRAS wt, and no prior EGFRmab), 8.7% were MSI-H. However, MSI-H prevalence differed markedly by KRAS mutation site: 8.8% of KRAS wt and 13.5-15.9% of codon 13/61/146 CRCs; but only 5.1% of codon 12 mutant CRCs were MSI-H (all p≤0.001). Notably, MSI-H also varied within KRAS codons: only 2.0% of G12C and 2.8% of G12V (both C&amp;gt;A) were MSI-H, vs 7.8% of G12D, 4.8% of G12A, and 3.8% of G12S. For confirmation of institutional findings, we analyzed data from a large reference laboratory. In Caris CODEai’s 83,532 nonBRAF V600E CRCs, 5.4% were MSI-H. Again, MSI-H prevalence varied by KRAS mutation site: 6.4% of KRAS wt, 5.6-6.9% of codon 13/61/117/146, and 19.2-26.9% of codon 14/59 mutant CRCs were MSI-H; compared to only 1.9% of codon 12 mut CRCs (all p&amp;lt;0.001). We then tested this finding in other cancer types in Caris CODEai. A similar result was observed in pancreatic cancer: among 40,497 only 0.7% were MSI-H, from 0.7% of KRAS wt to 0.4-0.5% of codon 12/61, but 7.8% of codon 13 (p&amp;lt;0.001). Conclusions: MSI-H prevalence varied by KRAS mutation location in CRC, with codon 12 muts—especially C&amp;gt;A—associated with low MSI-H rates, whereas codon 13/59/61/146 muts were enriched among MSI-H CRCs. Our data suggest that MSI/MMR mutational processes are associated with distinct codon-resolved KRAS biology and may give rise to specific KRAS muts, which warrants further investigation and could refine predictive biomarker interpretation. Citation Format: Mark Evans, Vishal Chandan, Kenna Shaw, Scott Kopetz, Anirban Maitra, Julian Bryan. Distinct KRAS mutation codons differentially associate with microsatellite instability in colorectal carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5336.