Abstract A043: Allele Specific Characteristics of KRAS Q61 Mutated Gastrointestinal Malignancies with Clinical Outcomes and Transcriptomic Features in Pancreatic Cancer
Sacha El Khoury, Mahmoud Yousef, Dan ZhaoAbstract
Background:
Pan-RAS and allele-specific inhibitors are entering clinical practice. Understanding KRAS-specific features is vital for therapy and overcoming resistance.
Methods:
We examined clinical and molecular traits of KRASQ61-mutated gastrointestinal cancers, especially pancreatic. Using Palantir Foundry, we queried survival and molecular data from CRC, PDAC, and other GI patients tested between 2002–2025. RNA-seq from prescision AI cohort of 578 external PDAC patients supported gene expression analysis. Another cohort of 145 patients who had RNA sequencing by BostonGene were analyzed for TME and gene expression features.
Results:
KRAS mutation was tested in 13,535 patient tumors at MDA. KRAS was mutated in 46.4% (n= 4,516) of CRC, 87.1% of PDAC (n=1,357), 18.4% of CC (n=100), 50.3% of AA (n=393), 7.3% of gastroesophageal carcinoma (n=51) and 7.4% of HCC (n=16). KRAS Q61 consisted of 5.3% (n=340) of KRAS mutation (n= 6,433). KRAS Q61H was the most common KRAS Q61 allele. The top co-mutated genes with KRAS were TP53 (71%) and APC (63%) for CRC, TP53 (76%) and CDKN2A (28%) for PDAC, GNAS (34%) and TP53 (34%) for AA and TP53 (30%) and ARID1A (19%) for CC. Patients with KRAS mutations had worse OS in CRC (50.8 vs. 63.7 months, HR=1.3, 95% CI 1.1–1.5, p=0.01) and PDAC (median OS 19.9 vs 38.7 months, HR=2.2, 95% CI=1.6-3.0, p<0.001). Compared to other KRAS mutations, KRAS Q61 had worse OS than other KRAS mutated PDAC patients (19.9 vs. 24.6 months, HR=1.3, 95% CI=1.0–1.7, p=0.049). RNA seq data from precision AI cohort (578 PDAC) tumors revealed transcriptional programs that were partly shared across KRAS-mutant tumors versus wildtype, and partly allele-specific, highlighting distinct pathway-level dysregulation associated with individual KRAS variants. Q61H showed pronounced hypoxia enrichment (Normalized Enrichment Score (NES)=+1.69, adjusted P value (padj)=5.7×10-5), comparable to G12D (NES=+1.61, padj=3.7×10-5) but absent in G12V (NES=−0.68, ns), suggesting unique biology and potential therapeutic vulnerabilities. Boston Gene analsysis showed KRAS mutated especially KRASQ61 mutated tumors, had more immunosuppressive, fibrotic TME and enrichment of hypoxia and TGF-β pathway gene expressions in PDAC.
Conclusions:
KRAS co-mutation landscape showed cancer specificities such as APC mutation in CRC, CDKN2A in PDAC, ARID1A for CC and GNAS mutations in AA. KRAS Q61 mutations varied across different GI malignancies. Allele-specific transcriptional programs were observed, with KRAS Q61H showing distinct hypoxia enrichment.
Citation Format:
Sacha El Khoury, Mahmoud Yousef, Dan Zhao. Allele Specific Characteristics of KRAS Q61 Mutated Gastrointestinal Malignancies with Clinical Outcomes and Transcriptomic Features in Pancreatic Cancer [abstract]. In: Proceedings of the AACR Conference on Pancreatic Cancer: New Frontiers in Biology and Therapeutic Development; 2026 Sep 25-28; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(18_Suppl_2):Abstract nr A043.