{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T09:00:40Z","timestamp":1785488440953,"version":"3.56.0"},"reference-count":35,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T00:00:00Z","timestamp":1785456000000},"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\/Objectives: Myeloproliferative neoplasms (MPNs) are chronic myeloid malignancies characterized by substantial genetic heterogeneity. Although routine molecular evaluation focuses on canonical driver alterations (BCR::ABL1, JAK2, CALR, and MPL), additional somatic mutations have important diagnostic and prognostic implications. Methods: We retrospectively analyzed 1209 consecutive patients who underwent peripheral blood next-generation sequencing (NGS) for suspected or established MPNs using a comprehensive 75-gene DNA\/RNA panel. Results: Canonical driver alterations were identified in 141 patients, while 1068 were driver-negative. Retrospective analysis demonstrated that 251 patients (21%) harbored at least one additional pathogenic or likely pathogenic mutation that was not routinely reported. Among driver-positive patients, 57 of 141 (40%) carried clinically relevant co-mutations, including high-molecular-risk genes such as ASXL1, TP53, SRSF2, SF3B1, RUNX1, U2AF1, and IDH2. Furthermore, 194 of 1068 (18%) driver-negative patients harbored additional pathogenic mutations, several of which supported clonal hematopoiesis or alternative myeloid neoplasms. Peripheral blood and bone marrow molecular findings demonstrated high concordance (R2 = 0.87). Conclusions: These findings indicate that comprehensive NGS performed at the time of initial evaluation provides clinically relevant genomic information beyond canonical driver mutations, improves disease classification and risk stratification, and may facilitate earlier diagnosis and personalized management of patients with suspected MPNs.<\/jats:p>","DOI":"10.3390\/cancers18152458","type":"journal-article","created":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T08:20:18Z","timestamp":1785486018000},"page":"2458","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Unmasking Additional Mutations: A Single Institution Study in Myeloproliferative Neoplasms"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1928-8967","authenticated-orcid":false,"given":"Parastou","family":"Tizro","sequence":"first","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6578-178X","authenticated-orcid":false,"given":"Eric","family":"Vail","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, 8723 Alden Drive, SSB-362, Los Angeles, CA 90048, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9987-1193","authenticated-orcid":false,"given":"Manoj","family":"Sapkota","sequence":"additional","affiliation":[{"name":"Department of Horticulture, University of Kentucky, Lexington, KY 40546, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-5701-9173","authenticated-orcid":false,"given":"Matthew G.","family":"Gayhart","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, 8723 Alden Drive, SSB-362, Los Angeles, CA 90048, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3857-9519","authenticated-orcid":false,"given":"Celeste C.","family":"Eno","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, 8723 Alden Drive, SSB-362, Los Angeles, CA 90048, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1200","DOI":"10.1182\/blood.2022015850","article-title":"International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: Integrating morphologic, clinical, and genomic data","volume":"140","author":"Arber","year":"2022","journal-title":"Blood"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1703","DOI":"10.1038\/s41375-022-01613-1","article-title":"The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic\/Dendritic Neoplasms","volume":"36","author":"Khoury","year":"2022","journal-title":"Leukemia"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.hoc.2020.11.005","article-title":"Epidemiology of the Philadelphia Chromosome-Negative Classical Myeloproliferative Neoplasms","volume":"35","author":"Shallis","year":"2021","journal-title":"Hematol. Oncol. Clin. N. Am."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1038\/s41375-018-0077-1","article-title":"Philadelphia chromosome-negative classical myeloproliferative neoplasms: Revised management recommendations from European LeukemiaNet","volume":"32","author":"Barbui","year":"2018","journal-title":"Leukemia"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2475","DOI":"10.1182\/blood-2017-06-782037","article-title":"Myeloproliferative neoplasms: From origins to outcomes","volume":"130","author":"Nangalia","year":"2017","journal-title":"Blood"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"7197","DOI":"10.1007\/s00432-023-04669-3","article-title":"Diagnosis and treatment of MPN in real life: Exploratory and retrospective chart review including 960 MPN patients diagnosed with ET or MF in Germany","volume":"149","author":"Schmidt","year":"2023","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1111\/bjh.12986","article-title":"Modification of British Committee for Standards in Haematology diagnostic criteria for essential thrombocythaemia","volume":"167","author":"Harrison","year":"2014","journal-title":"Br. J. Haematol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1001\/jama.2024.25349","article-title":"Essential Thrombocythemia: A Review","volume":"333","author":"Tefferi","year":"2025","journal-title":"JAMA"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1182\/bloodadvances.2016000208","article-title":"Targeted deep sequencing in primary myelofibrosis","volume":"1","author":"Tefferi","year":"2016","journal-title":"Blood Adv."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1182\/bloodadvances.2016000216","article-title":"Targeted deep sequencing in polycythemia vera and essential thrombocythemia","volume":"1","author":"Tefferi","year":"2016","journal-title":"Blood Adv."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1283","DOI":"10.1016\/j.mayocp.2017.06.002","article-title":"Genetic Risk Assessment in Myeloproliferative Neoplasms","volume":"92","author":"Tefferi","year":"2017","journal-title":"Mayo Clin. Proc."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2157","DOI":"10.1182\/blood-2013-11-536557","article-title":"Impact of mutational status on outcomes in myelofibrosis patients treated with ruxolitinib in the COMFORT-II study","volume":"123","author":"Guglielmelli","year":"2014","journal-title":"Blood"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1117","DOI":"10.1056\/NEJMoa1002028","article-title":"Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis","volume":"363","author":"Verstovsek","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1038\/s41408-018-0152-x","article-title":"Mutation landscape in patients with myelofibrosis receiving ruxolitinib or hydroxyurea","volume":"8","author":"Pacilli","year":"2018","journal-title":"Blood Cancer J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1056\/NEJMoa1412098","article-title":"Effect of mutation order on myeloproliferative neoplasms","volume":"372","author":"Ortmann","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e438","DOI":"10.3324\/haematol.2015.129510","article-title":"DNMT3A mutations occur early or late in patients with myeloproliferative neoplasms and mutation order influences phenotype","volume":"100","author":"Nangalia","year":"2015","journal-title":"Haematologica"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1934","DOI":"10.1182\/blood.2022017697","article-title":"JAK2 V617F allele burden in polycythemia vera: Burden of proof","volume":"141","author":"Moliterno","year":"2023","journal-title":"Blood"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1769","DOI":"10.1200\/JCO.2018.78.9867","article-title":"MIPSS70+ Version 2.0: Mutation and Karyotype-Enhanced International Prognostic Scoring System for Primary Myelofibrosis","volume":"36","author":"Tefferi","year":"2018","journal-title":"J. Clin. Oncol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1631","DOI":"10.1038\/s41375-018-0107-z","article-title":"GIPSS: Genetically inspired prognostic scoring system for primary myelofibrosis","volume":"32","author":"Tefferi","year":"2018","journal-title":"Leukemia"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1182\/asheducation-2017.1.489","article-title":"Current treatment algorithm for the management of patients with myelofibrosis, JAK inhibitors, and beyond","volume":"2017","author":"Harrison","year":"2017","journal-title":"Hematol. Am. Soc. Hematol. Educ. Program"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1200\/JCO.2017.76.4886","article-title":"MIPSS70: Mutation-Enhanced International Prognostic Score System for Transplantation-Age Patients With Primary Myelofibrosis","volume":"36","author":"Guglielmelli","year":"2018","journal-title":"J. Clin. Oncol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1111\/bjh.16380","article-title":"Mutation-enhanced international prognostic systems for essential thrombocythaemia and polycythaemia vera","volume":"189","author":"Tefferi","year":"2020","journal-title":"Br. J. Haematol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1007\/s11899-022-00685-1","article-title":"Molecular Pathogenesis of Myeloproliferative Neoplasms","volume":"17","author":"Rolles","year":"2022","journal-title":"Curr. Hematol. Malig. Rep."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/bs.ircmb.2021.02.008","article-title":"Mutational landscape of blast phase myeloproliferative neoplasms (MPN-BP) and antecedent MPN","volume":"366","author":"Pasca","year":"2022","journal-title":"Int. Rev. Cell Mol. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1186\/s13045-021-01116-z","article-title":"Molecular pathogenesis of the myeloproliferative neoplasms","volume":"14","author":"Greenfield","year":"2021","journal-title":"J. Hematol. Oncol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1952","DOI":"10.1038\/sj.leu.2404854","article-title":"Prospective identification of high-risk polycythemia vera patients based on JAK2(V617F) allele burden","volume":"21","author":"Vannucchi","year":"2007","journal-title":"Leukemia"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Gou, P., Zhang, W., and Giraudier, S. (2022). Insights into the Potential Mechanisms of JAK2V617F Somatic Mutation Contributing Distinct Phenotypes in Myeloproliferative Neoplasms. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23031013"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1007\/s12185-014-1670-3","article-title":"Molecular pathogenesis of atypical CML, CMML and MDS\/MPN-unclassifiable","volume":"101","author":"Zoi","year":"2015","journal-title":"Int. J. Hematol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2895","DOI":"10.1182\/blood-2008-07-170449","article-title":"New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment","volume":"113","author":"Cervantes","year":"2009","journal-title":"Blood"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1703","DOI":"10.1182\/blood-2009-09-245837","article-title":"A dynamic prognostic model to predict survival in primary myelofibrosis: A study by the IWG-MRT (International Working Group for Myeloproliferative Neoplasms Research and Treatment)","volume":"115","author":"Passamonti","year":"2010","journal-title":"Blood"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1200\/JCO.2010.32.2446","article-title":"DIPSS plus: A refined Dynamic International Prognostic Scoring System for primary myelofibrosis that incorporates prognostic information from karyotype, platelet count, and transfusion status","volume":"29","author":"Gangat","year":"2011","journal-title":"J. Clin. Oncol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1416","DOI":"10.1056\/NEJMoa1716614","article-title":"Classification and Personalized Prognosis in Myeloproliferative Neoplasms","volume":"379","author":"Grinfeld","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Jansko-Gadermeir, B., Leisch, M., Gassner, F.J., Zaborsky, N., Dillinger, T., Hutter, S., Risch, A., Melchardt, T., Egle, A., and Drost, M. (2023). Myeloid NGS Analyses of Paired Samples from Bone Marrow and Peripheral Blood Yield Concordant Results: A Prospective Cohort Analysis of the AGMT Study Group. Cancers, 15.","DOI":"10.3390\/cancers15082305"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"8091746","DOI":"10.1155\/2022\/8091746","article-title":"Concordance of Peripheral Blood and Bone Marrow Next-Generation Sequencing in Hematologic Neoplasms","volume":"2022","author":"Jumniensuk","year":"2022","journal-title":"Adv. Hematol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1002\/ajh.27658","article-title":"Targeted Therapies in Myelofibrosis: Present Landscape, Ongoing Studies, and Future Perspectives","volume":"100","author":"Loscocco","year":"2025","journal-title":"Am. J. Hematol."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/15\/2458\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T08:33:26Z","timestamp":1785486806000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/15\/2458"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,31]]},"references-count":35,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["cancers18152458"],"URL":"https:\/\/doi.org\/10.3390\/cancers18152458","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,31]]}}}