{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T21:46:59Z","timestamp":1792014419135,"version":"4.4.0"},"reference-count":29,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T00:00:00Z","timestamp":1762819200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Catholic Medical Center Research Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>KRAS mutations occur in over 90% of pancreatic ductal adenocarcinomas (PDACs), most commonly at codon 12, but the clinical implications of codon-specific subtypes in advanced disease remain unclear. We retrospectively analyzed 269 patients with advanced PDAC who underwent next-generation sequencing between 2020 and 2024 at a single tertiary cancer center. Clinical features, co-mutations, treatment outcomes, and survival were evaluated. KRAS mutations were detected in 92% of patients, most frequently G12V (36%) and G12D (34%), followed by G12R (10%) and non-G12 variants (9%). TP53 was the most frequent co-mutation (67%) and was significantly enriched in G12D tumors compared with wild type (74.2% vs. 31.8%). Mutations in homologous recombination and DNA damage response genes were more common in non-G12 and wild-type tumors, although not statistically significant. Serum CA 19-9 was elevated in most G12-mutant tumors, whereas approximately 40% of non-G12 and wild-type patients showed normal levels despite advanced disease. No significant survival differences were observed among KRAS subtypes in the overall or treated cohorts. However, patients with G12V mutations achieved significantly longer survival with fluorouracil-based than gemcitabine-based chemotherapy. These findings suggest that, while KRAS subtyping alone lacks prognostic value, the G12V subtype may inform chemotherapy selection and warrants further prospective validation.<\/jats:p>","DOI":"10.3390\/ijms262210908","type":"journal-article","created":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T08:57:41Z","timestamp":1762851461000},"page":"10908","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Clinical and Molecular Characteristics of KRAS Codon-Specific Mutations in Advanced Pancreatic Ductal Adenocarcinoma with Prognostic and Therapeutic Implications"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-2634-6866","authenticated-orcid":false,"given":"Dongwoo","family":"Cho","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Seoul St. Mary\u2019s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kabsoo","family":"Shin","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology, Department of Internal Medicine, Seoul St. Mary\u2019s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea"},{"name":"Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tae Ho","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of General Surgery, Seoul St. Mary\u2019s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1020-5838","authenticated-orcid":false,"given":"Sung Hak","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul St. Mary\u2019s Hospital, Seoul 06591, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4656-0188","authenticated-orcid":false,"given":"Younghoon","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul St. Mary\u2019s Hospital, Seoul 06591, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"In-Ho","family":"Kim","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology, Department of Internal Medicine, Seoul St. Mary\u2019s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea"},{"name":"Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4299-5694","authenticated-orcid":false,"given":"Sook-Hee","family":"Hong","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology, Department of Internal Medicine, Seoul St. Mary\u2019s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea"},{"name":"Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1204-0574","authenticated-orcid":false,"given":"MyungAh","family":"Lee","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology, Department of Internal Medicine, Seoul St. Mary\u2019s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea"},{"name":"Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5486-9818","authenticated-orcid":false,"given":"Se Jun","family":"Park","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology, Department of Internal Medicine, Seoul St. Mary\u2019s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea"},{"name":"Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,11]]},"reference":[{"key":"ref_1","first-page":"12","article-title":"Cancer statistics, 2024","volume":"74","author":"Siegel","year":"2024","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2008","DOI":"10.1016\/S0140-6736(20)30974-0","article-title":"Pancreatic cancer","volume":"395","author":"Mizrahi","year":"2020","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2785","DOI":"10.1002\/cncr.31551","article-title":"Annual Report to the Nation on the Status of Cancer, part I: National cancer statistics","volume":"124","author":"Cronin","year":"2018","journal-title":"Cancer"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1817","DOI":"10.1056\/NEJMoa1011923","article-title":"FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer","volume":"364","author":"Conroy","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1691","DOI":"10.1056\/NEJMoa1304369","article-title":"Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine","volume":"369","author":"Ervin","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1038\/nature11547","article-title":"Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes","volume":"491","author":"Biankin","year":"2012","journal-title":"Nature"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1038\/s43018-022-00349-2","article-title":"Translational advances in pancreatic ductal adenocarcinoma therapy","volume":"3","author":"Hosein","year":"2022","journal-title":"Nat. Cancer"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Cicenas, J., Kvederaviciute, K., Meskinyte, I., Meskinyte-Kausiliene, E., Skeberdyte, A., and Cicenas, J. (2017). KRAS, TP53, CDKN2A, SMAD4, BRCA1, and BRCA2 Mutations in Pancreatic Cancer. Cancers, 9.","DOI":"10.3390\/cancers9050042"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1038\/nature16965","article-title":"Genomic analyses identify molecular subtypes of pancreatic cancer","volume":"531","author":"Bailey","year":"2016","journal-title":"Nature"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1038\/s41698-024-00505-0","article-title":"Impact of KRAS mutations and co-mutations on clinical outcomes in pancreatic ductal adenocarcinoma","volume":"8","author":"Yousef","year":"2024","journal-title":"NPJ Precis. Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1038\/nrd.2016.139","article-title":"Direct small-molecule inhibitors of KRAS: From structural insights to mechanism-based design","volume":"15","author":"Ostrem","year":"2016","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2371","DOI":"10.1056\/NEJMoa2103695","article-title":"Sotorasib for Lung Cancers with KRAS p.G12C Mutation","volume":"384","author":"Skoulidis","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1056\/NEJMoa2204619","article-title":"Adagrasib in Non-Small-Cell Lung Cancer Harboring a KRAS(G12C) Mutation","volume":"387","author":"Riely","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1158\/2159-8290.CD-22-1066","article-title":"Efficacy of a Small-Molecule Inhibitor of KrasG12D in Immunocompetent Models of Pancreatic Cancer","volume":"13","author":"Kemp","year":"2023","journal-title":"Cancer Discov."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2171","DOI":"10.1038\/s41591-022-02007-7","article-title":"Anti-tumor efficacy of a potent and selective non-covalent KRAS(G12D) inhibitor","volume":"28","author":"Hallin","year":"2022","journal-title":"Nat. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1158\/2159-8290.CD-22-0035","article-title":"Classification of KRAS-Activating Mutations and the Implications for Therapeutic Intervention","volume":"12","author":"Johnson","year":"2022","journal-title":"Cancer Discov."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1158\/2159-8290.CD-19-0406","article-title":"RAS Mutations Are Not Created Equal","volume":"9","author":"Hobbs","year":"2019","journal-title":"Cancer Discov."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"100030","DOI":"10.1016\/j.esmogo.2023.100030","article-title":"Codon-specific KRAS mutations predict survival in advanced pancreatic cancer","volume":"3","author":"Rousseau","year":"2024","journal-title":"ESMO Gastrointest. Oncol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e157","DOI":"10.1038\/ctg.2016.18","article-title":"KRAS G12D Mutation Subtype Is A Prognostic Factor for Advanced Pancreatic Adenocarcinoma","volume":"7","author":"Bournet","year":"2016","journal-title":"Clin. Transl. Gastroenterol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1200\/JCO.2023.41.4_suppl.735","article-title":"Prognostic indicators of KRAS G12X mutations in pancreatic cancer","volume":"41","author":"Ardalan","year":"2023","journal-title":"J. Clin. Oncol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2094","DOI":"10.1158\/2159-8290.CD-20-1228","article-title":"Oncogenic KRAS Recruits an Expansive Transcriptional Network through Mutant p53 to Drive Pancreatic Cancer Metastasis","volume":"11","author":"Kim","year":"2021","journal-title":"Cancer Discov."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1016\/j.annonc.2020.10.601","article-title":"A transcriptomic signature to predict adjuvant gemcitabine sensitivity in pancreatic adenocarcinoma","volume":"32","author":"Nicolle","year":"2021","journal-title":"Ann. Oncol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1056\/NEJMoa2208470","article-title":"Sotorasib in KRAS p.G12C-Mutated Advanced Pancreatic Cancer","volume":"388","author":"Strickler","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Linehan, A., O\u2019Reilly, M., McDermott, R., and O\u2019Kane, G.M. (2024). Targeting KRAS mutations in pancreatic cancer: Opportunities for future strategies. Front. Med., 11.","DOI":"10.3389\/fmed.2024.1369136"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"113497","DOI":"10.1016\/j.ejca.2023.113497","article-title":"Precision medicine for KRAS wild-type pancreatic adenocarcinomas","volume":"197","author":"Rousseau","year":"2024","journal-title":"Eur. J. Cancer"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1016\/j.jmoldx.2016.10.002","article-title":"Standards and Guidelines for the Interpretation and Reporting of Sequence Variants in Cancer: A Joint Consensus Recommendation of the Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists","volume":"19","author":"Li","year":"2017","journal-title":"J. Mol. Diagn."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Jeong, S.H., Kyung, D., Yuk, H.D., Jeong, C.W., Lee, W., Yoon, J.K., Kim, H.P., Bang, D., Kim, T.Y., and Lim, Y. (2023). Practical Utility of Liquid Biopsies for Evaluating Genomic Alterations in Castration-Resistant Prostate Cancer. Cancers, 15.","DOI":"10.3390\/cancers15102847"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3239","DOI":"10.1158\/1078-0432.CCR-20-0418","article-title":"Genomic Methods Identify Homologous Recombination Deficiency in Pancreas Adenocarcinoma and Optimize Treatment Selection","volume":"26","author":"Park","year":"2020","journal-title":"Clin. Cancer Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1200\/PO.17.00286","article-title":"Prevalence of Homologous Recombination-Related Gene Mutations Across Multiple Cancer Types","volume":"2","author":"Heeke","year":"2018","journal-title":"JCO Precis. Oncol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/22\/10908\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T09:00:02Z","timestamp":1762851602000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/22\/10908"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,11]]},"references-count":29,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["ijms262210908"],"URL":"https:\/\/doi.org\/10.3390\/ijms262210908","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,11]]}}}