{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T02:35:41Z","timestamp":1791513341817,"version":"4.3.4"},"reference-count":38,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2025,8,8]],"date-time":"2025-08-08T00:00:00Z","timestamp":1754611200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health, NIH, National Cancer Institute, NCI","award":["U2CCA252971"],"award-info":[{"award-number":["U2CCA252971"]}]},{"name":"National Institutes of Health, NIH, National Cancer Institute, NCI","award":["P30CA033572"],"award-info":[{"award-number":["P30CA033572"]}]},{"name":"National Institutes of Health, NIH, National Cancer Institute, NCI","award":["U54CA285116"],"award-info":[{"award-number":["U54CA285116"]}]},{"name":"City of Hope Cancer Control and Population Sciences program by the National Institutes of Health, NIH, National Cancer Institute, NCI","award":["U2CCA252971"],"award-info":[{"award-number":["U2CCA252971"]}]},{"name":"City of Hope Cancer Control and Population Sciences program by the National Institutes of Health, NIH, National Cancer Institute, NCI","award":["P30CA033572"],"award-info":[{"award-number":["P30CA033572"]}]},{"name":"City of Hope Cancer Control and Population Sciences program by the National Institutes of Health, NIH, National Cancer Institute, NCI","award":["U54CA285116"],"award-info":[{"award-number":["U54CA285116"]}]},{"name":"Drug Development and Capacity Building: A UCR\/CoH-CCC Partnership project by the National Institutes of Health, NIH, National Cancer Institute, NCI","award":["U2CCA252971"],"award-info":[{"award-number":["U2CCA252971"]}]},{"name":"Drug Development and Capacity Building: A UCR\/CoH-CCC Partnership project by the National Institutes of Health, NIH, National Cancer Institute, NCI","award":["P30CA033572"],"award-info":[{"award-number":["P30CA033572"]}]},{"name":"Drug Development and Capacity Building: A UCR\/CoH-CCC Partnership project by the National Institutes of Health, NIH, National Cancer Institute, NCI","award":["U54CA285116"],"award-info":[{"award-number":["U54CA285116"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Pancreatic cancer (PC) is a highly aggressive malignancy with increasing incidence and poor survival. Hispanic\/Latino (H\/L) patients, despite having a lower overall incidence than Non-Hispanic White (NHW) patients, are often diagnosed younger and at more advanced stages, leading to worse outcomes. The molecular mechanisms underlying these disparities remain unclear. This study characterizes mutations in key oncogenic pathways\u2014TP53, WNT, PI3K, TGF-Beta, and RTK\/RAS\u2014among H\/L and NHW patients using publicly available datasets. We analyzed genomic data from 4248 PC patients (407 H\/L; 3841 NHW), comparing mutation frequencies across pathways. Chi-squared tests assessed group differences, and Kaplan\u2013Meier analysis evaluated survival outcomes by pathway alterations. TGF-Beta pathway mutations were less common in H\/L patients (18.4% vs. 24.4%, p = 8.6 \u00d7 10\u22123), with notable differences in SMAD2 (1.5% vs. 0.4%, p = 6.3 \u00d7 10\u22123) and SMAD4 (15% vs. 19.9%, p = 0.02). While overall differences in other pathways were not statistically significant, several genes showed borderline significance, including ERBB4, ALK, HRAS, RIT1 (RTK\/RAS), and CTNNB1 (WNT). No significant survival differences were observed in H\/L patients, but NHW patients with TP53 alterations showed borderline survival associations. This study reveals ethnicity-specific pathway alterations in PC, with SMAD2, ERBB4, ALK, and CTNNB1 mutations being more frequent in H\/L patients, while SMAD4 and PI3K alterations had prognostic value in NHW patients. These findings indicate the importance of incorporating ethnicity-specific molecular profiling into precision oncology for PC.<\/jats:p>","DOI":"10.3390\/ijms26167695","type":"journal-article","created":{"date-parts":[[2025,8,8]],"date-time":"2025-08-08T15:30:52Z","timestamp":1754667052000},"page":"7695","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Pathway-Specific Genomic Alterations in Pancreatic Cancer Across Populations at Risk"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5558-2744","authenticated-orcid":false,"given":"Cecilia","family":"Monge","sequence":"first","affiliation":[{"name":"Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-5991-9779","authenticated-orcid":false,"given":"Brigette","family":"Waldrup","sequence":"additional","affiliation":[{"name":"Department of Integrative Translational Sciences, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1789-4197","authenticated-orcid":false,"given":"Francisco G.","family":"Carranza","sequence":"additional","affiliation":[{"name":"Department of Integrative Translational Sciences, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophia","family":"Manjarrez","sequence":"additional","affiliation":[{"name":"Department of Integrative Translational Sciences, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3603-6414","authenticated-orcid":false,"given":"Enrique","family":"Velazquez-Villarreal","sequence":"additional","affiliation":[{"name":"Department of Integrative Translational Sciences, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA"},{"name":"City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1038\/s41575-019-0109-y","article-title":"Molecular subtypes of pancreatic cancer","volume":"16","author":"Collisson","year":"2019","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_2","unstructured":"Program NCISR (2025, January 10). SEER Explorer: An Interactive Website for SEER Cancer Statistics, Available online: https:\/\/seer.cancer.gov\/explorer\/."},{"key":"ref_3","first-page":"12","article-title":"Cancer statistics, 2024","volume":"74","author":"Siegel","year":"2024","journal-title":"CA Cancer J. Clin."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1097\/SLA.0000000000001763","article-title":"Multi-institutional Validation Study of the American Joint Commission on Cancer (8th Edition) Changes for T and N Staging in Patients With Pancreatic Adenocarcinoma","volume":"265","author":"Allen","year":"2017","journal-title":"Ann. Surg."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"16022","DOI":"10.1038\/nrdp.2016.22","article-title":"Pancreatic cancer","volume":"2","author":"Kleeff","year":"2016","journal-title":"Nat. Rev. Dis. Primers."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3131","DOI":"10.1007\/s40615-022-01486-1","article-title":"Health Disparities in Presentation, Treatment, Genomic Testing, and Outcomes of Pancreatic Cancer in Hispanic and Non-Hispanic Patients","volume":"10","author":"Halder","year":"2023","journal-title":"J. Racial Ethn. Health Disparities"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1482","DOI":"10.2337\/dc21-1543","article-title":"Diabetes Incidence Among Hispanic\/Latino Adults in the Hispanic Community Health Study\/Study of Latinos (HCHS\/SOL)","volume":"45","author":"Cordero","year":"2022","journal-title":"Diabetes Care"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1093\/jnci\/djy090","article-title":"Pancreatic Cancer Following Incident Diabetes in African Americans and Latinos: The Multiethnic Cohort","volume":"111","author":"Setiawan","year":"2019","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e171","DOI":"10.1097\/MPA.0000000000002408","article-title":"Somatic Genomic Profiling of Pancreatic Ductal Adenocarcinomas From a Diverse Cohort of Patients","volume":"54","author":"Riner","year":"2025","journal-title":"Pancreas"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Baba, A.B., Rah, B., Bhat, G.R., Mushtaq, I., Parveen, S., Hassan, R., Hameed Zargar, M., and Afroze, D. (2022). Transforming Growth Factor-Beta (TGF-\u03b2) Signaling in Cancer-A Betrayal Within. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.791272"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1186\/s13578-017-0168-0","article-title":"TGF-\u03b2 in pancreatic cancer initiation and progression: Two sides of the same coin","volume":"7","author":"Shen","year":"2017","journal-title":"Cell Biosci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1080\/1061186X.2023.2274806","article-title":"Signalling in pancreatic cancer: From pathways to therapy","volume":"31","author":"Zhou","year":"2023","journal-title":"J. Drug Target."},{"key":"ref_13","unstructured":"Cancer Genome Atlas Research Network (2017). Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma. Cancer Cell, 32, 185\u2013203.e13."},{"key":"ref_14","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_15","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1053\/j.gastro.2021.09.022","article-title":"Genomic and Molecular Analyses Identify Molecular Subtypes of Pancreatic Cancer Recurrence","volume":"162","author":"Dreyer","year":"2022","journal-title":"Gastroenterology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"5363","DOI":"10.1038\/sj.onc.1202909","article-title":"The TGF-beta signaling inhibitor Smad7 enhances tumorigenicity in pancreatic cancer","volume":"18","author":"Kleeff","year":"1999","journal-title":"Oncogene"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"269","DOI":"10.31083\/j.fbl2907269","article-title":"Knockdown of TGF-\u03b2 in Pancreatic Cancer Helps Ameliorate Gemcitabine Resistance","volume":"29","author":"Wang","year":"2024","journal-title":"Front. Biosci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"154603","DOI":"10.1016\/j.prp.2023.154603","article-title":"The KRAS signaling pathway\u2019s impact on the characteristics of pancreatic cancer cells","volume":"248","author":"Chen","year":"2023","journal-title":"Pathol. Res. Pract."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"799","DOI":"10.32604\/or.2024.045356","article-title":"Targeting KRAS in pancreatic cancer","volume":"32","author":"Stickler","year":"2024","journal-title":"Oncol. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1158\/1078-0432.CCR-23-2098","article-title":"A Small Molecule with Big Impact: MRTX1133 Targets the KRASG12D Mutation in Pancreatic Cancer","volume":"30","author":"Wei","year":"2024","journal-title":"Clin. Cancer Res."},{"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":"742","DOI":"10.1136\/gutjnl-2018-316822","article-title":"Combating pancreatic cancer with PI3K pathway inhibitors in the era of personalised medicine","volume":"68","author":"Conway","year":"2019","journal-title":"Gut"},{"key":"ref_23","first-page":"104","article-title":"Portrait of the PI3K\/AKT pathway in colorectal cancer","volume":"1855","author":"Danielsen","year":"2015","journal-title":"Biochim. Biophys. Acta."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Stanciu, S., Ionita-Radu, F., Stefani, C., Miricescu, D., Stanescu-Spinu, I.I., Greabu, M., Ripszky Totan, A., and Jinga, M. (2022). Targeting PI3K\/AKT\/mTOR Signaling Pathway in Pancreatic Cancer: From Molecular to Clinical Aspects. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms231710132"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1016\/j.ccell.2020.05.010","article-title":"Altered RNA Splicing by Mutant p53 Activates Oncogenic RAS Signaling in Pancreatic Cancer","volume":"38","author":"Penson","year":"2020","journal-title":"Cancer Cell"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"188556","DOI":"10.1016\/j.bbcan.2021.188556","article-title":"Tumor suppressor p53: Biology, signaling pathways, and therapeutic targeting","volume":"1876","year":"2021","journal-title":"Biochim. Biophys. Acta. Rev. Cancer"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1038\/s41392-023-01347-1","article-title":"Targeting p53 pathways: Mechanisms, structures, and advances in therapy","volume":"8","author":"Wang","year":"2023","journal-title":"Signal Transduc. Target Ther."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.jbior.2018.06.002","article-title":"Introduction of WT-TP53 into pancreatic cancer cells alters sensitivity to chemotherapeutic drugs, targeted therapeutics and nutraceuticals","volume":"69","author":"Abrams","year":"2018","journal-title":"Adv. Biol. Regul."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"McCubrey, J.A., Yang, L.V., Abrams, S.L., Steelman, L.S., Follo, M.Y., Cocco, L., Ratti, S., Martelli, A.M., Augello, G., and Cervello, M. (2022). Effects of TP53 Mutations and miRs on Immune Responses in the Tumor Microenvironment Important in Pancreatic Cancer Progression. Cells, 11.","DOI":"10.3390\/cells11142155"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2464","DOI":"10.2174\/13816128112092464","article-title":"Role of Wnt\/\u03b2-catenin signaling in drug resistance of pancreatic cancer","volume":"18","author":"Cui","year":"2012","journal-title":"Curr. Pharm. Des."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"671022","DOI":"10.3389\/fcell.2021.671022","article-title":"WNT Ligand Dependencies in Pancreatic Cancer","volume":"9","author":"Aguilera","year":"2021","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1801","DOI":"10.1126\/science.1164368","article-title":"Core signaling pathways in human pancreatic cancers revealed by global genomic analyses","volume":"321","author":"Jones","year":"2008","journal-title":"Science"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Carranza, F.G., Diaz, F.C., Ninova, M., and Velazquez-Villarreal, E. (2024). Current state and future prospects of spatial biology in colorectal cancer. Front. Oncol., 14.","DOI":"10.3389\/fonc.2024.1513821"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Waldrup, B., Carranza, F., Jin, Y., Amzaleg, Y., Postel, M., Craig, D.W., Carpten, J.D., Salhia, B., Ricker, C.N., and Culver, J.O. (2024). Integrative multi-omics profiling of colorectal cancer from a Hispanic\/Latino cohort of patients. medRxiv, medRxiv:2024.11.03.24316599.","DOI":"10.1101\/2024.11.03.24316599"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Zhao, S., Agyare, E., Zhu, X., Trevino, J., Rogers, S., Velazquez-Villarreal, E., Brant, J., Eliahoo, P., Barajas, J., and Hoang, B. (2025). ECM Stiffness-Induced Redox Signaling Enhances Stearoyl-Gemcitabine Efficacy in Pancreatic Cancer. Cancers, 17.","DOI":"10.3390\/cancers17050870"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1038\/s42003-020-1044-8","article-title":"Single-cell sequencing of genomic DNA resolves sub-clonal heterogeneity in a melanoma cell line","volume":"3","author":"Maheshwari","year":"2020","journal-title":"Commun. Biol."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Monge, C., Waldrup, B., Carranza, F.G., and Velazquez-Villarreal, E. (2025). Comparative Genomic Analysis of Key Oncogenic Pathways in Hepatocellular Carcinoma Among Diverse Populations. Cancers, 17.","DOI":"10.1101\/2025.02.27.25323065"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Monge, C., Waldrup, B., Carranza, F.G., and Velazquez-Villarreal, E. (2025). Molecular Alterations in TP53, WNT, PI3K, TGF-Beta, and RTK\/RAS Pathways in Gastric Cancer Among Ethnically Heterogeneous Cohorts. Cancers, 17.","DOI":"10.1101\/2025.02.22.25322719"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/16\/7695\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:26:53Z","timestamp":1760034413000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/16\/7695"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,8]]},"references-count":38,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2025,8]]}},"alternative-id":["ijms26167695"],"URL":"https:\/\/doi.org\/10.3390\/ijms26167695","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,8]]}}}