{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T13:15:04Z","timestamp":1768569304856,"version":"3.49.0"},"posted":{"date-parts":[[2025,2,5]]},"group-title":"Oncology","reference-count":40,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,2,5]],"date-time":"2025-02-05T00:00:00Z","timestamp":1738713600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.medrxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,2,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Introduction<\/jats:title>\n                  <jats:p>\n                    While\n                    <jats:italic>KRAS<\/jats:italic>\n                    mutations represent the primary oncogenic driver in pancreatic ductal adenocarcinoma (PDAC), the association between codon-specific alterations and patient outcomes remains poorly elucidated, largely due to a lack of datasets coupling genomic profiling with rich clinical annotations across disease stages.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Patients and Methods<\/jats:title>\n                  <jats:p>\n                    We utilized AACR\u2019s GENIE Biopharma Consortium Pancreas v1.2 dataset to test the associating of codon-specific\n                    <jats:italic>KRAS<\/jats:italic>\n                    mutations with clinicogenomic features and patient outcomes in PDAC patients diagnosed with localized (stages I-III) and advanced disease (stage IV). Overall survival was compared using Kaplan\u2013Meier and multivariable Cox proportional hazards methods.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    Among 1,032 eligible patients, 949 (92%) exhibited mutant\n                    <jats:italic>KRAS<\/jats:italic>\n                    . These mutations were predominantly observed at G12D (n=390, 41%), G12V (n=305, 32%), and G12R (n=149, 16%). In the group of patients who presented with localized disease, those with G12V mutation had notably longer survival compared to G12D mutation (\n                    <jats:italic>P<\/jats:italic>\n                    = 0.002). In contrast, patients with G12V mutation who presented with metastatic disease experienced shorter overall survival compared to those with G12R (\n                    <jats:italic>P<\/jats:italic>\n                    = 0.005), and G12D mutations (\n                    <jats:italic>P<\/jats:italic>\n                    = 0.009). Furthermore, no significant differences were observed in the frequencies of co-altered driver genes, including\n                    <jats:italic>TP53<\/jats:italic>\n                    ,\n                    <jats:italic>CDKN2A<\/jats:italic>\n                    , and\n                    <jats:italic>SMAD4<\/jats:italic>\n                    , across the different\n                    <jats:italic>KRAS<\/jats:italic>\n                    mutations.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>\n                    These findings demonstrated that codon-specific\n                    <jats:italic>KRAS<\/jats:italic>\n                    mutations impact PDAC outcomes differently based on disease stage at diagnosis. As studies testing\n                    <jats:italic>KRAS<\/jats:italic>\n                    inhibitors continue to emerge and mature, these data offer important contextual insights regarding survival outcomes associated with codon-specific\n                    <jats:italic>KRAS<\/jats:italic>\n                    mutations based on existing therapeutic approaches.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.02.03.25321601","type":"posted-content","created":{"date-parts":[[2025,2,5]],"date-time":"2025-02-05T19:15:25Z","timestamp":1738782925000},"source":"Crossref","is-referenced-by-count":0,"title":["Prognostic Implications of Codon-Specific\n                  <i>KRAS<\/i>\n                  Mutations in Localized and Advanced Stages of Pancreatic Cancer"],"prefix":"10.64898","author":[{"given":"Sara","family":"Raji","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hamed","family":"Zaribafzadeh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tyler","family":"Jones","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elishama","family":"Kanu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kunling","family":"Tong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ashley","family":"Fletcher","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"T. Clark","family":"Howell","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shannon J.","family":"McCall","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeffrey R.","family":"Marks","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bruce","family":"Rogers","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Donna","family":"Niedzwiecki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter J.","family":"Allen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel P.","family":"Nussbaum","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zahra","family":"Kabiri","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025020700400780000_2025.02.03.25321601v1.1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21590"},{"key":"2025020700400780000_2025.02.03.25321601v1.2","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2021.4708"},{"key":"2025020700400780000_2025.02.03.25321601v1.3","doi-asserted-by":"publisher","DOI":"10.1038\/s43018-022-00349-2"},{"key":"2025020700400780000_2025.02.03.25321601v1.4","doi-asserted-by":"publisher","DOI":"10.3390\/cancers14102417"},{"key":"2025020700400780000_2025.02.03.25321601v1.5","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13215510"},{"key":"2025020700400780000_2025.02.03.25321601v1.6","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2022.1074538"},{"key":"2025020700400780000_2025.02.03.25321601v1.7","doi-asserted-by":"publisher","DOI":"10.1038\/s41698-024-00505-0"},{"key":"2025020700400780000_2025.02.03.25321601v1.8","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.abn2694"},{"key":"2025020700400780000_2025.02.03.25321601v1.9","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-20-0442"},{"key":"2025020700400780000_2025.02.03.25321601v1.10","doi-asserted-by":"publisher","DOI":"10.1200\/po.24.00263"},{"key":"2025020700400780000_2025.02.03.25321601v1.11","doi-asserted-by":"publisher","DOI":"10.1001\/jamasurg.2015.0313"},{"key":"2025020700400780000_2025.02.03.25321601v1.12","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.5607"},{"key":"2025020700400780000_2025.02.03.25321601v1.13","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.2017.37"},{"key":"2025020700400780000_2025.02.03.25321601v1.14","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.33038"},{"key":"2025020700400780000_2025.02.03.25321601v1.15","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2017.3420"},{"key":"2025020700400780000_2025.02.03.25321601v1.16","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2024.08.002"},{"key":"2025020700400780000_2025.02.03.25321601v1.17","doi-asserted-by":"publisher","DOI":"10.2147\/ott.S279312"},{"key":"2025020700400780000_2025.02.03.25321601v1.18","doi-asserted-by":"publisher","DOI":"10.1038\/ctg.2016.18"},{"key":"2025020700400780000_2025.02.03.25321601v1.19","doi-asserted-by":"publisher","DOI":"10.1200\/po.22.00570"},{"key":"2025020700400780000_2025.02.03.25321601v1.20","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-17-0151"},{"key":"2025020700400780000_2025.02.03.25321601v1.21","doi-asserted-by":"publisher","DOI":"10.1200\/CCI.20.00108"},{"key":"2025020700400780000_2025.02.03.25321601v1.22","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-23-0580"},{"key":"2025020700400780000_2025.02.03.25321601v1.23","doi-asserted-by":"publisher","DOI":"10.1200\/CCI.21.00105"},{"key":"2025020700400780000_2025.02.03.25321601v1.24","doi-asserted-by":"publisher","DOI":"10.1002\/cam4.2895"},{"key":"2025020700400780000_2025.02.03.25321601v1.25","doi-asserted-by":"publisher","DOI":"10.1093\/oncolo\/oyac179"},{"key":"2025020700400780000_2025.02.03.25321601v1.26","doi-asserted-by":"publisher","DOI":"10.1158\/1541-7786.MCR-15-0203"},{"key":"2025020700400780000_2025.02.03.25321601v1.27","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-19-1006"},{"key":"2025020700400780000_2025.02.03.25321601v1.28","doi-asserted-by":"publisher","DOI":"10.1021\/acs.biochem.9b00532"},{"key":"2025020700400780000_2025.02.03.25321601v1.29","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-18-1220"},{"key":"2025020700400780000_2025.02.03.25321601v1.30","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-018-0076-6"},{"key":"2025020700400780000_2025.02.03.25321601v1.31","doi-asserted-by":"publisher","DOI":"10.1200\/jco.23.00434"},{"key":"2025020700400780000_2025.02.03.25321601v1.32","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2208470"},{"key":"2025020700400780000_2025.02.03.25321601v1.33","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.1c01688"},{"key":"2025020700400780000_2025.02.03.25321601v1.34","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06123-3"},{"key":"2025020700400780000_2025.02.03.25321601v1.35","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-24-0027"},{"key":"2025020700400780000_2025.02.03.25321601v1.36","unstructured":"Holderfield M , Lee BJ , Jiang J , Tomlinson A , Seamon KJ , Mira A , et al. Concurrent inhibition of oncogenic and wild-type RAS-GTP for cancer therapy. 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