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Background KRAS inhibitors showed promising results in clinical trials. Understanding KRAS mutations and immune regulation is critical for more effective and durable KRAS targeted therapy. KRAS Q61 is rare and less studied in cancer patients. Here we investigate the clinical, molecular, tumor microenvironment (TME) features of KRASQ61 mutated gastrointestinal (GI) malignancies.Methods We used the Palantir Foundry system to query electronic health records of patients diagnosed with colorectal (CRC), pancreatic (PDAC), appendiceal (AA), cholangiocarcinoma (CC), hepatocellular carcinoma (HCC) and gastroesophageal cancer who were tested for KRAS mutations in our institution between 2002-2025. Clinical, molecular, and overall survival (OS) data were collected and studied. Subsets of PDAC and CRC patients had tumoral bulk RNA sequencing and their TME characteristics were analyzed.Results KRAS mutation was tested in 13,535 patients with CRC, PDAC, CC, AA, and gastroesophageal cancer. 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). KRASQ61 consisted of 5.3% (n=340) of KRAS mutation (n= 6,433). Frequencies of KRASQ61 was 2.2% (n=210) for CRC, 6.2% (n=97) for PDAC, 2.4% (n= 13) for CC, 2% (n= 16) for AA and 0.6% (n= 4) for gastroesophageal carcinoma. KRASQ61H was the most common KRASQ61 allele. The top mutated genes 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. Compared to KRAS wildtype, patients with KRAS mutations had worse OS in CRC (p<0.05), while longer OS was noticed in KRAS mutated AA patients (p<0.05). Compared to other KRAS mutations, KRAS Q61 had worse OS in PDAC than other KRAS mutated PDAC and wildtype patients (19.9 months for KRASQ61 , 24.6 months for other KRAS mutated and 38.7 months for wildtype, p<0.05). KRAS mutated tumors, especially KRAS Q61 mutated tumors, had more immunosuppressive, fibrotic TME than KRAS wildtype tumors and showed enrichment of hypoxia and TGF-β pathway gene expression in PDAC.Conclusions KRAS Q61 mutations frequency varied across different GI malignancies, with the highest frequency in PDAC (6.2%). 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 had worse OS in patients with PDAC and more immune suppressive and fibrotic TME and enrichment of hypoxia and TGF-β pathway expression.Consent The informed consent was waived, as per the IRB guidelines for retrospective studies on clinical and molecular information.Ethics Approval The MD Anderson Cancer Center institutional review board approved the collection of demographic, clinical, and pathological information under the Institutional Review Board (IRB) protocol Lab09-0373 and 2023-0091.