{"doi":"10.1200/po.21.00245","title":"Landscape of <i>KRAS</i><sup>G12C</sup>, Associated Genomic Alterations, and Interrelation With Immuno-Oncology Biomarkers in <i>KRAS</i>-Mutated Cancers","abstract":"<jats:sec><jats:title>PURPOSE</jats:title><jats:p> Promising single-agent activity from sotorasib and adagrasib in KRAS<jats:sup>G12C</jats:sup>-mutant tumors has provided clinical evidence of effective KRAS signaling inhibition. However, comprehensive analysis of KRAS-variant prevalence, genomic alterations, and the relationship between KRAS and immuno-oncology biomarkers is lacking. </jats:p></jats:sec><jats:sec><jats:title>MATERIALS AND METHODS</jats:title><jats:p> Retrospective analysis of deidentified records from 79,004 patients with various cancers who underwent next-generation sequencing was performed. Fisher's exact test evaluated the association between cancer subtypes and KRAS variants. Logistic regression assessed KRAS<jats:sup>G12C</jats:sup> comutations with other oncogenes and the association between KRAS variants and immuno-oncology biomarkers. </jats:p></jats:sec><jats:sec><jats:title>RESULTS</jats:title><jats:p> Of the 79,004 samples assessed, 13,758 (17.4%) harbored KRAS mutations, with 1,632 (11.9%) harboring KRAS<jats:sup>G12C</jats:sup> and 12,126 (88.1%) harboring other KRAS variants ( KRAS<jats:sup>non-G12C</jats:sup>). Compared with KRAS<jats:sup>non-G12C</jats:sup> across all tumor subtypes, KRAS<jats:sup>G12C</jats:sup> was more prevalent in females (56% v 51%, false discovery rate-adjusted P value [FDR- P] = .0006), current or prior smokers (85% v 56%, FDR- P &lt; .0001), and patients age &gt; 60 years (73% v 63%, FDR- P ≤ .0001). The most frequent KRAS variants across all subtypes were G12D (29.5%), G12V (23.0%), G12C (11.9%), G13D (6.5%), and G12R (6.2%). KRAS<jats:sup>G12C</jats:sup> was most prevalent in patients with non–small-cell lung cancer (9%), appendiceal (3.9%), colorectal (3.2%), tumor of unknown origin (1.6%), small bowel (1.43%), and pancreatic (1.3%) cancers. Compared with KRAS<jats:sup>non-G12C</jats:sup>-mutated, KRAS<jats:sup>G12C</jats:sup>-mutated tumors were significantly associated with tumor mutational burden-high status (17.9% v 8.4%, odds ratio [OR] = 2.38; FDR- P &lt; .0001). KRAS<jats:sup>G12C</jats:sup>-mutated tumors exhibited a distinct comutation profile from KRAS<jats:sup>non-G12C</jats:sup>-mutated tumors, including higher comutations of STK11 (20.59% v 5.95%, OR = 4.10; FDR- P &lt; .01) and KEAP1 (15.38% v 4.61%, OR = 3.76; FDR- P &lt; .01). </jats:p></jats:sec><jats:sec><jats:title>CONCLUSION</jats:title><jats:p> This study presents the first large-scale, pan-cancer genomic characterization of KRAS<jats:sup>G12C</jats:sup>. The KRAS<jats:sup>G12C</jats:sup> mutation was more prevalent in females and older patients and appeared to be associated with smoking status. KRAS<jats:sup>G12C</jats:sup> tumors exhibited a distinct comutation profile and were associated with tumor mutational burden-high status. </jats:p></jats:sec>","journal":"JCO Precision Oncology","year":2022,"id":634963,"datarank":0.687745121800586,"base_score":4.584967478670572,"endowment":4.584967478670572,"self_citation_contribution":0.687745121800586,"citation_network_contribution":0.0,"self_endowment_contribution":0.687745121800586,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":97,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1647087,"name":"Sherif M. El-Refai","orcid":"0000-0003-2080-4172","position":1,"is_corresponding":false},{"id":594939,"name":"Wei Sha","orcid":"0000-0002-5453-859X","position":2,"is_corresponding":false},{"id":254336,"name":"Alberto Puccini","orcid":"0000-0002-2492-4043","position":3,"is_corresponding":false},{"id":254338,"name":"Axel Grothey","orcid":"0000-0002-9341-6499","position":4,"is_corresponding":false},{"id":263950,"name":"Thomas J. George","orcid":"0000-0002-6249-9180","position":5,"is_corresponding":false},{"id":335458,"name":"Jimmy J. Hwang","orcid":null,"position":6,"is_corresponding":false},{"id":1647093,"name":"Bert O'Neil","orcid":null,"position":7,"is_corresponding":false},{"id":1647095,"name":"Alexander S. Barrett","orcid":null,"position":8,"is_corresponding":false},{"id":1437204,"name":"Kunal C. Kadakia","orcid":"0000-0003-3574-4141","position":9,"is_corresponding":false},{"id":600974,"name":"Laura W. Musselwhite","orcid":"0000-0003-0505-801X","position":10,"is_corresponding":false},{"id":7933,"name":"Derek Raghavan","orcid":"0000-0002-7358-3994","position":11,"is_corresponding":false},{"id":88015,"name":"Eric Van Cutsem","orcid":"0000-0002-6372-1230","position":12,"is_corresponding":false},{"id":35283,"name":"Josep Tabernero","orcid":"0000-0002-2495-8139","position":13,"is_corresponding":false},{"id":275543,"name":"Jeanne Tie","orcid":"0000-0001-9244-2057","position":14,"is_corresponding":false},{"id":254334,"name":"Mohamed E. Salem","orcid":"0000-0002-3661-6785","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Landscape of <i>KRAS</i><sup>G12C</sup>, Associated Genomic Alterations, and Interrelation With Immuno-Oncology Biomarkers in <i>KRAS</i>-Mutated Cancers","abstract":"<jats:sec><jats:title>PURPOSE</jats:title><jats:p> Promising single-agent activity from sotorasib and adagrasib in KRAS<jats:sup>G12C</jats:sup>-mutant tumors has provided clinical evidence of effective KRAS signaling inhibition. However, comprehensive analysis of KRAS-variant prevalence, genomic alterations, and the relationship between KRAS and immuno-oncology biomarkers is lacking. </jats:p></jats:sec><jats:sec><jats:title>MATERIALS AND METHODS</jats:title><jats:p> Retrospective analysis of deidentified records from 79,004 patients with various cancers who underwent next-generation sequencing was performed. Fisher's exact test evaluated the association between cancer subtypes and KRAS variants. Logistic regression assessed KRAS<jats:sup>G12C</jats:sup> comutations with other oncogenes and the association between KRAS variants and immuno-oncology biomarkers. </jats:p></jats:sec><jats:sec><jats:title>RESULTS</jats:title><jats:p> Of the 79,004 samples assessed, 13,758 (17.4%) harbored KRAS mutations, with 1,632 (11.9%) harboring KRAS<jats:sup>G12C</jats:sup> and 12,126 (88.1%) harboring other KRAS variants ( KRAS<jats:sup>non-G12C</jats:sup>). Compared with KRAS<jats:sup>non-G12C</jats:sup> across all tumor subtypes, KRAS<jats:sup>G12C</jats:sup> was more prevalent in females (56% v 51%, false discovery rate-adjusted P value [FDR- P] = .0006), current or prior smokers (85% v 56%, FDR- P &lt; .0001), and patients age &gt; 60 years (73% v 63%, FDR- P ≤ .0001). The most frequent KRAS variants across all subtypes were G12D (29.5%), G12V (23.0%), G12C (11.9%), G13D (6.5%), and G12R (6.2%). KRAS<jats:sup>G12C</jats:sup> was most prevalent in patients with non–small-cell lung cancer (9%), appendiceal (3.9%), colorectal (3.2%), tumor of unknown origin (1.6%), small bowel (1.43%), and pancreatic (1.3%) cancers. Compared with KRAS<jats:sup>non-G12C</jats:sup>-mutated, KRAS<jats:sup>G12C</jats:sup>-mutated tumors were significantly associated with tumor mutational burden-high status (17.9% v 8.4%, odds ratio [OR] = 2.38; FDR- P &lt; .0001). KRAS<jats:sup>G12C</jats:sup>-mutated tumors exhibited a distinct comutation profile from KRAS<jats:sup>non-G12C</jats:sup>-mutated tumors, including higher comutations of STK11 (20.59% v 5.95%, OR = 4.10; FDR- P &lt; .01) and KEAP1 (15.38% v 4.61%, OR = 3.76; FDR- P &lt; .01). </jats:p></jats:sec><jats:sec><jats:title>CONCLUSION</jats:title><jats:p> This study presents the first large-scale, pan-cancer genomic characterization of KRAS<jats:sup>G12C</jats:sup>. The KRAS<jats:sup>G12C</jats:sup> mutation was more prevalent in females and older patients and appeared to be associated with smoking status. KRAS<jats:sup>G12C</jats:sup> tumors exhibited a distinct comutation profile and were associated with tumor mutational burden-high status. </jats:p></jats:sec>","is_dataset_classified":null,"base_score":4.584967478670572,"endowment":4.584967478670572,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"35319967","pmcid":"PMC8966967","openalex_id":"https://openalex.org/W4220717021","authors":[],"funders":[],"total_grants":0,"fwci":6.9729,"citation_percentile":0.98231925,"influential_citations":0,"citation_trend":[{"year":2022,"count":12},{"year":2023,"count":24},{"year":2024,"count":30},{"year":2025,"count":23},{"year":2026,"count":8}],"oa_status":"hybrid","license":"cc-by","oa_locations":[{"url":"https://doi.org/10.1200/po.21.00245","host_type":"journal"},{"url":"https://doi.org/10.1200/po.21.00245","host_type":"publisher"},{"url":"https://ascopubs.org/doi/pdfdirect/10.1200/PO.21.00245","host_type":"publisher"},{"url":"https://pubmed.ncbi.nlm.nih.gov/35319967","host_type":"repository"},{"url":"https://lirias.kuleuven.be/handle/20.500.12942/703628","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/8966967","host_type":"repository"},{"url":"https://lirias.kuleuven.be/retrieve/f514659d-3f95-4798-8517-670c1e3209cd","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC8966967","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC8966967?pdf=render","host_type":"Europe_PMC"}],"fields_of_study":["Protein Kinase Regulation and GTPase Signaling","Receptor Mechanisms and Signaling","HER2/EGFR in Cancer Research"],"mesh_terms":["Kelch-Like ECH-Associated Protein 1","Acetonitriles","Carcinoma, Non-Small-Cell Lung","Female","Humans","Lung Neoplasms","Middle Aged","Piperazines","Pyrimidines","Retrospective Studies","Biomarkers, Tumor","Proto-Oncogene Proteins p21(ras)","Genomics","NF-E2-Related Factor 2"],"keywords":["Mutation","Cancer","Genome","Disease","Genomics"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[{"name":"nct"},{"name":"doi"}],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-06T14:26:15.313789Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}