{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T15:34:59Z","timestamp":1773329699500,"version":"3.50.1"},"reference-count":32,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2025,2,19]],"date-time":"2025-02-19T00:00:00Z","timestamp":1739923200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: Intraductal papillary mucinous neoplasms (IPMNs) are pre-malignant pancreatic lesions that may progress to invasive pancreatic ductal adenocarcinoma (PDAC). IPMN-associated invasive carcinoma (iIPMN) has been associated with more favorable survival outcomes compared to non-iIPMN-derived PDAC. Here, we aim to investigate the genetic landscape of IPMNs to assess their relevance to oncologic outcomes. Methods: This retrospective study used a large single-institution prospectively maintained database. Patients who underwent curative-intent pancreatic resection between 2016 and 2022 with histologically confirmed diagnosis of IPMN were included. Demographic, pathologic, molecular, and oncologic outcome data were recorded. Kaplan\u2013Meier survival analyses were performed. PDAC data from public genetic databases were used for mutational correlation analysis. p-value \u2264 0.05 was considered as significant. Results: A total of thirty-nine patients with resected IPMN with complete clinical and sequencing data were identified and included in the final cohort. The male-to-female distribution was 21:18, and the mean age was 70.1 \u00b1 9.1 years. GNAS mutations occurred in 23.1% of patients, and 89.7% of patients had iIPMN. In iIPMN patients, GNAS mutation was strongly associated with improved disease-free survival: all GNAS-mutant patients survived to follow-up with significantly fewer recurrences than in GNAS wild-type (WT) patients (p = 0.013). Mutated GNAS closely co-occurred with wild-type KRAS (p &lt; 0.001), and further analysis of large genomic PDAC datasets validated this finding (OR 3.47, p &lt; 0.0001). Conclusions: Our study suggests prognostic value of mutational status in malignant resected IPMNs. WT GNAS, mutant P53, and mutant KRAS each correlate with recurrence and decreased survival. Further studies are required to validate these preliminary observations.<\/jats:p>","DOI":"10.3390\/cancers17040705","type":"journal-article","created":{"date-parts":[[2025,2,19]],"date-time":"2025-02-19T08:36:46Z","timestamp":1739954206000},"page":"705","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Correlation of GNAS Mutational Status with Oncologic Outcomes in Patients with Resected Intraductal Papillary Mucinous Neoplasms"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-6461-3759","authenticated-orcid":false,"given":"Julia","family":"Evans","sequence":"first","affiliation":[{"name":"Sidney Kimmel Medical College, Philadelphia, PA 19107, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kylee","family":"Shivok","sequence":"additional","affiliation":[{"name":"Sidney Kimmel Medical College, Philadelphia, PA 19107, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0769-9083","authenticated-orcid":false,"given":"Hui Hsuan","family":"Chen","sequence":"additional","affiliation":[{"name":"Sidney Kimmel Medical College, Philadelphia, PA 19107, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5265-4909","authenticated-orcid":false,"given":"Eliyahu","family":"Gorgov","sequence":"additional","affiliation":[{"name":"Jefferson Pancreas, Biliary and Related Cancer Center, Sidney Kimmel Cancer Center, Philadelphia, PA 19107, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wilbur B.","family":"Bowne","sequence":"additional","affiliation":[{"name":"Jefferson Pancreas, Biliary and Related Cancer Center, Sidney Kimmel Cancer Center, Philadelphia, PA 19107, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9383-7501","authenticated-orcid":false,"given":"Aditi","family":"Jain","sequence":"additional","affiliation":[{"name":"Jefferson Pancreas, Biliary and Related Cancer Center, Sidney Kimmel Cancer Center, Philadelphia, PA 19107, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Harish","family":"Lavu","sequence":"additional","affiliation":[{"name":"Jefferson Pancreas, Biliary and Related Cancer Center, Sidney Kimmel Cancer Center, Philadelphia, PA 19107, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8097-0071","authenticated-orcid":false,"given":"Charles J.","family":"Yeo","sequence":"additional","affiliation":[{"name":"Jefferson Pancreas, Biliary and Related Cancer Center, Sidney Kimmel Cancer Center, Philadelphia, PA 19107, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5928-0559","authenticated-orcid":false,"given":"Avinoam","family":"Nevler","sequence":"additional","affiliation":[{"name":"Jefferson Pancreas, Biliary and Related Cancer Center, Sidney Kimmel Cancer Center, Philadelphia, PA 19107, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e5535","DOI":"10.1097\/MD.0000000000005535","article-title":"Incidental Pancreatic Cystic Neoplasms in an Asymptomatic Healthy Population of 21,745 Individuals Large-Scale, Single-Center Cohort Study","volume":"95","author":"Chang","year":"2016","journal-title":"Medicine"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1001\/archsurg.138.4.427","article-title":"Incidental Pancreatic Cysts: Clinicopathologic Characteristics and Comparison with Symptomatic Patients","volume":"138","author":"Targarona","year":"2003","journal-title":"Arch. Surg."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1007\/s13304-019-00661-0","article-title":"The Diagnosis and Management of Intraductal Papillary Mucinous Neoplasms of the Pancreas: Has Progress Been Made?","volume":"71","author":"Lim","year":"2019","journal-title":"Updat. Surg."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e2337799","DOI":"10.1001\/jamanetworkopen.2023.37799","article-title":"Long-Term Outcomes and Risk of Pancreatic Cancer in Intraductal Papillary Mucinous Neoplasms","volume":"6","author":"Chatterjee","year":"2023","journal-title":"JAMA Netw. Open"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1053\/j.gastro.2007.05.010","article-title":"Branch-Duct Intraductal Papillary Mucinous Neoplasms: Observations in 145 Patients Who Underwent Resection","volume":"133","author":"Rodriguez","year":"2007","journal-title":"Gastroenterology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1002\/bjs5.50156","article-title":"Management and Outcomes of Intraductal Papillary Mucinous Neoplasms","volume":"3","author":"Hipp","year":"2019","journal-title":"BJS Open"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1097\/01.sla.0000124386.54496.15","article-title":"Main-Duct Intraductal Papillary Mucinous Neoplasms of the Pancreas: Clinical Predictors of Malignancy and Long-Term Survival Following Resection","volume":"239","author":"Salvia","year":"2004","journal-title":"Ann. Surg."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1309","DOI":"10.1016\/j.ejso.2021.12.009","article-title":"IPMN-Associated Pancreatic Cancer: Survival, Prognostic Staging and Impact of Adjuvant Chemotherapy","volume":"48","author":"Kaiser","year":"2021","journal-title":"Eur. J. Surg. Oncol. (EJSO)"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"962","DOI":"10.1097\/SLA.0000000000004147","article-title":"Actual Five-year Survival After Upfront Resection for Pancreatic Ductal Adenocarcinoma: Who Beats the Odds?","volume":"275","author":"Strobel","year":"2020","journal-title":"Ann. Surg."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1007\/s00428-015-1751-6","article-title":"GNAS Mutation is a Frequent Event in Pancreatic Intraductal Papillary Mucinous Neoplasms and Associated Adenocarcinomas","volume":"466","author":"Hosoda","year":"2015","journal-title":"Virchows Arch."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-020-74868-2","article-title":"GNAS Mutation Detection in Circulating Cell-Free DNA Is a Specific Predictor for Intraductal Papillary Mucinous Neoplasms of the Pancreas, Especially for Intestinal Subtype","volume":"10","author":"Hata","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"92ra66","DOI":"10.1126\/scitranslmed.3002543","article-title":"Recurrent GNAS Mutations Define an Unexpected Pathway for Pancreatic Cyst Development","volume":"3","author":"Wu","year":"2011","journal-title":"Sci. Transl. Med."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Furukawa, T., Kuboki, Y., Tanji, E., Yoshida, S., Hatori, T., Yamamoto, M., Shibata, N., Shimizu, K., Kamatani, N., and Shiratori, K. (2011). Whole-Exome Sequencing Uncovers Frequent GNAS Mutations in Intraductal Papillary Mucinous Neoplasms of the Pancreas. Sci. Rep., 1.","DOI":"10.1038\/srep00161"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2131","DOI":"10.1136\/gutjnl-2016-313586","article-title":"Preoperative Next-Generation Sequencing of Pancreatic Cyst Fluid Is Highly Accurate in Cyst Classification and Detection of Advanced Neoplasia","volume":"67","author":"Singhi","year":"2018","journal-title":"Gut"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3802","DOI":"10.1245\/s10434-013-3096-1","article-title":"Clinicopathological Correlates of Activating GNAS Mutations in Intraductal Papillary Mucinous Neoplasm (IPMN) of the Pancreas","volume":"20","author":"Molin","year":"2013","journal-title":"Ann. Surg. Oncol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1172","DOI":"10.1186\/s40064-016-2847-4","article-title":"KRAS, GNAS, and RNF43 Mutations in Intraductal Papillary Mucinous Neoplasm of the Pancreas: A Meta-Analysis","volume":"5","author":"Lee","year":"2016","journal-title":"SpringerPlus"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2640","DOI":"10.1245\/s10434-019-07389-6","article-title":"GNAS but Not Extended RAS Mutations Spectrum are Associated with a Better Prognosis in Intraductal Pancreatic Mucinous Neoplasms","volume":"26","author":"Gaujoux","year":"2019","journal-title":"Ann. Surg. Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.1053\/j.gastro.2019.06.001","article-title":"Intraductal Papillary Mucinous Neoplasms Arise from Multiple Independent Clones, Each with Distinct Mutations","volume":"157","author":"Fischer","year":"2019","journal-title":"Gastroenterology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"980","DOI":"10.5858\/arpa.2023-0358-RA","article-title":"Neoplastic Progression in Macroscopic Precursor Lesions of the Pancreas","volume":"148","author":"Thompson","year":"2024","journal-title":"Arch. Pathol. Lab. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1007\/s00423-017-1644-z","article-title":"Can We Better Predict the Biologic Behavior of Incidental IPMN? A Comprehensive Analysis of Molecular Diagnostics and Biomarkers in Intraductal Papillary Mucinous Neoplasms of the Pancreas","volume":"403","author":"Tulla","year":"2017","journal-title":"Langenbeck\u2019s Arch. Surg."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1016\/j.jamcollsurg.2014.11.029","article-title":"GNAS and KRAS Mutations Define Separate Progression Pathways in Intraductal Papillary Mucinous Neoplasm-Associated Carcinoma","volume":"220","author":"Tan","year":"2015","journal-title":"J. Am. Coll. Surg."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"652","DOI":"10.1016\/j.ejim.2015.07.016","article-title":"Malignant Transformation and Overall Survival of Morphological Subtypes of Intraductal Papillary Mucinous Neoplasms of the Pancreas: A Network Meta-Analysis","volume":"26","author":"Qi","year":"2015","journal-title":"Eur. J. Intern. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1097\/SLA.0b013e318287ab73","article-title":"Pathohistological Subtype Predicts Survival in Patients with Intraductal Papillary Mucinous Neoplasm (IPMN) of the Pancreas","volume":"258","author":"Distler","year":"2013","journal-title":"Ann. Surg."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1016\/j.surg.2009.11.011","article-title":"Invasive Carcinoma Derived from the Nonintestinal Type Intraductal Papillary Mucinous Neoplasm of the Pancreas Has a Poorer Prognosis Than That Derived from the Intestinal Type","volume":"147","author":"Sadakari","year":"2010","journal-title":"Surgery"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1097\/MPA.0b013e318214fa86","article-title":"Invasive Carcinoma Derived from Intestinal-Type Intraductal Papillary Mucinous Neoplasm Is Associated with Minimal Invasion, Colloid Carcinoma, and Less Invasive Behavior, Leading to a Better Prognosis","volume":"40","author":"Nakata","year":"2011","journal-title":"Pancreas"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1108","DOI":"10.1097\/SLA.0000000000001008","article-title":"Patterns of Recurrence After Resection of IPMN: Who, When, and How?","volume":"262","author":"Marchegiani","year":"2015","journal-title":"Ann. Surg."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Asano, G., Miyabe, K., Kato, H., Yoshida, M., Sawada, T., Okamoto, Y., Sahashi, H., Atsuta, N., Kachi, K., and Kato, A. (2022). Relevance of Gene Mutations and Methylation to the Growth of Pancreatic Intraductal Papillary Mucinous Neoplasms Based on Pyrosequencing. Sci. Rep., 12.","DOI":"10.1038\/s41598-021-04335-z"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1097\/MPA.0000000000000258","article-title":"Clinical Significance of GNAS Mutation in Intraductal Papillary Mucinous Neoplasm of the Pancreas with Concomitant Pancreatic Ductal Adenocarcinoma","volume":"44","author":"Ideno","year":"2015","journal-title":"Pancreas"},{"key":"ref_29","first-page":"8061","article-title":"Intraductal Papillary Mucinous Neoplasms of the Pancreas: Clinical Association with KRAS","volume":"17","author":"Chang","year":"2018","journal-title":"Mol. Med. Rep."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1200\/JCO.2024.42.3_suppl.698","article-title":"The Impact of Wnt Pathway Alterations Including RNF43, GNAS, CTNNB1, and APC on Prognosis and Potential Therapeutic Vulnerability in Pancreatic Adenocarcinoma (PDAC)","volume":"42","author":"Takebe","year":"2024","journal-title":"J. Clin. Oncol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1002\/path.2875","article-title":"Molecular Characteristics and Biological Behaviours of the Oncocytic and Pancreatobiliary Subtypes of Intraductal Papillary Mucinous Neoplasms","volume":"224","author":"Xiao","year":"2011","journal-title":"J. Pathol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/j.pan.2023.12.009","article-title":"International Evidence-Based Kyoto Guidelines for the Management of Intraductal Papillary Mucinous Neoplasm of the Pancreas","volume":"24","author":"Ohtsuka","year":"2024","journal-title":"Pancreatology"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/17\/4\/705\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:37:56Z","timestamp":1760027876000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/17\/4\/705"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,19]]},"references-count":32,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2025,2]]}},"alternative-id":["cancers17040705"],"URL":"https:\/\/doi.org\/10.3390\/cancers17040705","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,19]]}}}